Dihydropyrazolopyrimidinone derivatives

ABSTRACT

The invention relates to compounds of a general formula (I): 
     
       
         
         
             
             
         
       
     
     wherein Ar 1  is an optionally-substituted aryl or heteroaromatic group; R 1  is an optionally-substituted lower alkyl, lower alkenyl, lower alkynyl or cyclo-lower alkyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R 2  is a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower alkynyl group, or is an aryl, aralkyl or heteroaromatic group optionally having a substituent; R 3  is a hydrogen atom or a lower alkyl group; R 4  is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group or a group of —N(R 1k )R 1m ; T and U are a nitrogen atom or a methine group, etc. 
     The compounds of the invention have excellent Weel kinase-inhibitory effect and are therefore useful in the field of medicines, especially treatment of various cancers.

TECHNICAL FIELD

The present invention is useful in the field of medicine. Moreprecisely, the dihydropyrazolopyrimidinone derivatives of the inventionare useful in the field of treatment of various cancers as a kinaseinhibitor, especially as a Weel kinase inhibitor.

BACKGROUND ART

Cells have a checkpoint mechanism of such that, when the DNA therein isdamaged, then the cells temporarily stop the cell cycle and repair thedamaged DNA (Cell Proliferation, Vol. 33, pp. 261-274). In about a halfof human cancers, a cancer-suppressor gene, p53 is mutated or depletedand the cells thereby have lost the G1 checkpoint function thereof.However, such cancer cells still keep the G2 checkpoint functionremaining therein, which is considered to be one factor of lowering thesensitivity of the cells to DNA-active anticancer agents and toradiations.

A Weel kinase is a tyrosine kinase that participates in the G2checkpoint of a cell cycle. Weel phosphorylates Cdc2(Cdk1) tyrosine 15that participates in the progress to the M stage from the G2 stage in acell cycle, thereby inactivating Cdc2 and temporarily stopping the cellcycle at the G2 stage (The EMBO Journal, Vol. 12, pp. 75-85).Accordingly, in cancer cells having lost the p53 function therein, it isconsidered that the G2 checkpoint function by Weel is important forrepairing the damaged DNA so as to evade the cell death. Heretofore, ithas been reported that the Weel expression reduction by RNA interferenceor the Weel inhibition by compounds may increase the sensitivity ofcancer cells to adriamycin, X ray and gamma ray (Cancer Biology &Therapy, Vol. 3, pp. 305-313; Cancer Research, Vol. 61, pp. 8211-8217).From the above, it is considered that a Weel inhibitor may inhibit theG2 checkpoint function of p53-depleted cancer cells, thereby enhancingthe sensitivity of the cells to DNA-active anticancer agents and toradiations.

As a low-molecular Weel kinase inhibitor, for example, known arecompounds described in US Application 2005/0250836, WO2003/091255,Cancer Research, Vol. 61, pp. 8211-8217, or Bioorg & Med. Chem. Lett.,Vol. 15, pp. 1931-1935. However, the compounds described in thesereferences quite differ from the compounds of the invention in point oftheir structures.

On the other hand, WO2004/056786 or WO2005/021532 or WO2006/091737disclose various compounds such as dihydropyrazolopyridines that arerelatively similar to the compounds of the invention in point of theirskeletons. However, these references do neither concretely disclose norsuggest any Weel kinase-inhibitory effect of those compounds as well asthe compounds of the invention.

DISCLOSURE OF INVENTION

An object of the invention is to provide a novel anticancer agent havinga kinase-inhibitory effect, especially a Wed kinase-inhibitory effect.

As a result of assiduous studies, the present inventors have found thatcompounds of the following general formula (I) have an excellentkinase-inhibitory effect, especially an excellent Weel kinase-inhibitoryeffect, and have completed the present invention:

wherein;

A¹ is an aryl group or a heteroaromatic group, which may have asubstituent selected from a group consisting of a halogen atom, a loweralkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group, alower alkoxy group, a lower alkanoyl group, a hydroxy-lower alkylaminogroup, a carbamoyl group, a hydroxy-lower alkylcarbamoyl group, aheteroaromatic group optionally substituted by a lower alkyl group, anda group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b);

A¹ is a single bond, an oxygen atom or a sulfur atom, or is an iminogroup optionally substituted by a lower alkyl group;

A² is a nitrogen atom, or is a methine or 1-vinyl-2-ylidene groupoptionally substituted by a hydroxyl group, a lower alkyl group or ahydroxy-lower alkyl group;

Q¹ is a single bond, a carbonyl group, or a methylene group optionallysubstituted by a lower alkyl group;

Q² is a single bond, or an ethylene group optionally substituted by alower alkyl group;

R^(1a) and R^(1b) are independently a hydrogen atom, a lower alkyl groupor a hydroxy-lower alkyl group, or together form a lower alkylene groupwherein one or two or more methylene groups constituting the loweralkylene group may be independently replaced by an oxygen atom, a sulfuratom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylenegroup or a group of —N(R^(1c))—, and/or substituted by a hydroxyl groupor a lower alkyl group;

R^(1c) is a hydrogen atom, a lower alkenyl group or a group of-Q³-A³(R^(1d))R^(1e);

A³ is a nitrogen atom, or is a methine or 1-vinyl-2-ylidene groupoptionally substituted by a hydroxyl group, a lower alkyl group or ahydroxy-lower alkyl group;

Q³ is a single bond or a lower alkylene group, wherein one or two ormore methylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom, a sulfur atom, a carbonylgroup, a sulfinyl group or a sulfonyl group, and/or substituted by ahalogen atom, a cyano group, a hydroxyl group or a lower alkyl group;

R^(1d) and R^(1e) are independently a hydrogen atom, a halogen atom, acyano group, a hydroxyl group, a lower alkyl group or a hydroxy-loweralkyl group, or together form a lower alkylene group wherein one or twoor more methylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom, a sulfur atom, a sulfinylgroup, a sulfonyl group, a carbonyl group, a vinylene group or a groupof —N(R^(1f))—, and/or substituted by a hydroxyl group or a lower alkylgroup;

R^(1f) is a hydrogen atom, a lower alkyl group, a halo-lower alkylgroup, a lower alkenyl group or a lower alkanoyl group;

R¹ is a lower alkyl group, a lower alkenyl group, a lower alkynyl groupor a cyclo-lower alkyl group optionally substituted by a halogen atom,or is an aryl group, an aralkyl group or a heteroaromatic groupoptionally having a substituent selected from a group consisting of ahalogen atom, a cyano group, an amino group and a lower alkyl group;

-   -   R² is a hydrogen atom, a lower alkyl group, a lower alkenyl        group or a lower alkynyl group, or is an aryl group, an aralkyl        group or a heteroaromatic group optionally having a substituent        selected from a group consisting of a halogen atom, a cyano        group, a nitro group, a carboxyl group, a group of        -Q⁴-A⁴(R^(1g))R^(1h) and a group of -Q⁵-Ar^(a), wherein one or        two or more methylene groups constituting the lower alkyl group,        the lower alkenyl group or the lower alkynyl group may be        independently replaced by an oxygen atom, a sulfur atom, a        sulfinyl group, a sulfonyl group, a carbonyl group or a group of        —N(R^(1j))—, and/or substituted by a halogen atom;

A⁴ is a nitrogen atom, or is a methine group optionally substituted by ahalogen atom, a hydroxyl group, a lower alkyl group or a hydroxy-loweralkyl group;

Ar^(a) is an aryl group or a heteroaromatic group, which may have asubstituent selected from a group consisting of a halogen atom, a loweralkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group and alower alkoxy group;

Q⁴ is a single bond or a lower alkylene group, wherein one or two ormore methylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom or a carbonyl group, and/orsubstituted by a lower alkyl group;

Q⁵ is a single bond, an oxygen atom, a sulfur atom, a carbonyl group ora lower alkylene group, wherein one or two or more methylene groupsconstituting the lower alkylene group may be independently replaced byan oxygen atom, a sulfur atom or a carbonyl group, and/or substituted bya halogen atom or a lower alkyl group;

R^(1g) and R^(1h) are independently a hydrogen atom, a halogen atom, acyano group, a hydroxyl group, a lower alkyl group, a lower alkoxy-loweralkyl group, a lower alkanoyl group, a lower alkoxycarbonyl group or alower alkylsulfonyl group, or together form a lower alkylene group,wherein one or two or more methylene groups constituting the loweralkylene group may be independently replaced by an oxygen atom, a sulfuratom, a sulfinyl group, a sulfonyl group, a carbonyl group or a group of—N(R^(1i))—, and/or substituted by a halogen atom or a lower alkylgroup;

R^(1i) is a hydrogen atom, a lower alkyl group or a halo-lower alkylgroup;

R^(1j) is a hydrogen atom or a lower alkyl group;

R³ is a hydrogen atom or a lower alkyl group;

R⁴ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkylgroup or a group of —N(R^(1k))R^(1m);

R^(1k) and R^(1m) are independently a hydrogen atom or a lower alkylgroup;

T and U are independently a nitrogen atom or a methine group, providedthat the compounds wherein R¹ is a methyl group and R² is anunsubstituted phenyl group are excluded.

The compounds (I) of the invention have a kinase-inhibitory effect,especially a Weel kinase-inhibitory effect, and are therefore useful asremedies for various cancers such as brain cancer, cervicocerebralcancer, esophageal cancer, thyroid cancer, small cell cancer, non-smallcell cancer, breast cancer, lung cancer, stomach cancer,gallbladder/bile duct cancer, liver cancer, pancreatic cancer, coloncancer, rectal cancer, ovarian cancer, choriocarcinoma, uterus bodycancer, uterocervical cancer, renal pelvis/ureter cancer, bladdercancer, prostate cancer, penis cancer, testicles cancer, fetal cancer,Wilms' cancer, skin cancer, malignant melanoma, neuroblastoma,osteosarcoma, Ewing's tumor, soft part sarcoma, acute leukemia, chroniclymphatic leukemia, chronic myelocytic leukemia, Hodgkin's lymphoma.

In particular, the compounds (I) of the invention are useful asremedies, for example, for breast cancer, lung cancer, pancreaticcancer, colon cancer, ovarian cancer, acute leukemia, chronic lymphaticleukemia, chronic myelocytic leukemia, Hodgkin's lymphoma.

The invention relates to the compounds of formula (I), their salts andesters, as well as to their production methods and their use.

The meanings of the terms used in this description are described below,and the invention is described in more detail hereinunder.

“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atomand an iodine atom.

“Lower alkyl group” means a linear or branched alkyl group having from 1to 6 carbon atoms, including, for example, a methyl group, an ethylgroup, a propyl group, an isopropyl group, a butyl group, an isobutylgroup, a sec-butyl group, a tert-butyl group, a pentyl group, anisopentyl group, a hexyl group, an isohexyl group.

“Halo-lower alkyl group” means the above-mentioned lower alkyl group inwhich any substitutable position is substituted by one or two or more,preferably from 1 to 3, the same or different, above-mentioned halogenatoms, including, for example, a fluoromethyl group, a difluoromethylgroup, a trifluoromethyl group, a 2-fluoroethyl group, a1,2-difluoroethyl group, a chloromethyl group, a 2-chloroethyl group, a1,2-dichloroethyl group, a bromomethyl group, an iodomethyl group.

“Hydroxy-lower alkyl group” means the above-mentioned lower alkyl groupin which any substitutable position is substituted by one or two ormore, preferably 1 or 2 hydroxyl groups, including, for example, ahydroxymethyl group, a 2-hydroxyethyl group, a 1-hydroxy-1-methylethylgroup, a 1,2-dihydroxyethyl group, a 3-hydroxypropyl group.

“Lower alkoxy group” means a linear or branched alkoxy group having from1 to 6 carbon atoms, including, for example, a methoxy group, an ethoxygroup, a propoxy group, an isopropoxy group, a butoxy group, asec-butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxygroup, an isopentyloxy group, a hexyloxy group, an isohexyloxy group.

“Lower alkanoyl group” means an alkanoyl group having theabove-mentioned lower alkyl group, or that is, an alkanoyl group havingfrom 2 to 7 carbon atoms, including, for example, an acetyl group, apropionyl group, a butyryl group, an isobutyryl group, a valeryl group,an isovaleryl group, a pivaloyl group.

“Hydroxy-lower alkylamino group” means an amino group mono- ordi-substituted, preferably mono-substituted by the above-mentionedhydroxy-lower alkyl group; including, for example, a hydroxymethylaminogroup, a 2-hydroxyethylamino group, a 1-hydroxy-1-methylethylaminogroup, a 1,2-dihydroxyethylamino group, a 3-hydroxypropylamino group.

“Hydroxy-lower alkylcarbamoyl group” means a carbamoyl group mono- ordi-substituted, preferably mono-substituted by the above-mentionedhydroxy-lower alkyl group, including, for example, ahydroxymethylcarbamoyl group, a 2-hydroxyethylcarbamoyl group, a1-hydroxy-1-methylethylcarbamoyl group, a 1,2-dihydroxyethylcarbamoylgroup, a 3-hydroxypropylcarbamoyl group.

“Aryl group” includes, for example, a phenyl group, a naphthyl group.

“Heteroaromatic group” means a 5-membered or 6-membered monocyclicaromatic heterocyclic group having one or two or more, preferably from 1to 3, the same or different hetero atoms selected from a groupconsisting of an oxygen atom, a nitrogen atom and a sulfur atom; or acondensed cyclic aromatic heterocyclic group formed through condensationof that monocyclic aromatic heterocyclic group and the above-mentionedaryl group, or through condensation of the same or different suchmonocyclic aromatic heterocyclic groups; and it includes, for example, apyrrolyl group, a furyl group, a thienyl group, an imidazolyl group, apyrazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolylgroup, an isoxazolyl group, a triazolyl group, a tetrazolyl group, anoxadiazolyl group, a 1,2,3-thiadiazolyl group, a 1,2,4-thiadiazolylgroup, a 1,3,4-thiadiazolyl group, a pyridyl group, a pyrazinyl group, apyrimidinyl group, a pyridazinyl group, a 1,2,4-triazinyl group, a1,3,5-triazinyl group, an indolyl group, a benzofuranyl group, abenzothienyl group, a benzimidazolyl group, a benzoxazolyl group, abenzisoxazolyl group, a benzothiazolyl group, a benzisothiazolyl group,an indazolyl group, a purinyl group, a quinolyl group, an isoquinolylgroup, a phthalazinyl group, a naphthyridinyl group, a quinoxalinylgroup, a quinazolinyl group, a cinnolinyl group, a pteridinyl group, apyrido[3,2-b]pyridyl group.

“Lower alkylene group” means a linear or branched alkylene group havingfrom 1 to 6 carbon atoms, including, for example, a methylene group, anethylene group, a trimethylene group, a tetramethylene group, apentamethylene group, a hexamethylene group.

“Lower alkenyl group” means a linear or branched alkenyl group havingfrom 2 to 6 carbon atoms, including, for example, a vinyl group, a1-propenyl group, an allyl group, an isopropenyl group, a 3-butenylgroup, a 2-butenyl group, a 1-butenyl group, a 1-methyl-2-propenylgroup, a 1-methyl-1-propenyl group, a 1-ethyl-1-ethenyl group, a2-methyl-2-propenyl group, a 2-methyl-1-propenyl group, a3-methyl-2-butenyl group, a 4-pentenyl group.

“Lower alkynyl group” means a linear or branched alkynyl group havingfrom 2 to 6 carbon atoms, including, for example, an ethynyl group, a1-propynyl group, a 2-propynyl group, a 3-butynyl, group, a 2-butynylgroup, a 1-butynyl group, a 1-methyl-2-propynyl group, a1-ethyl-2-propynyl group, a 1-methyl-2-butynyl group, a 4-pentynylgroup.

“Cyclo-lower alkyl group” means a cycloalkyl group having from 3 to 6carbon atoms, including, for example, a cyclopropyl group, a cyclobutylgroup, a cyclopentyl group, a cyclohexyl group.

“Aralkyl group” means the above-mentioned alkyl group in which anysubstitutable position is substituted by one or two or more, preferablyone, above-mentioned aryl groups, including, for example, a benzylgroup, a 1-phenylethyl group, a phenethyl group, a 1-naphthylmethylgroup, a 2-naphthylmethyl group.

“Lower alkoxy-lower alkyl group” means the above-mentioned lower alkylgroup in which any substitutable position is substituted by one or twoor more, preferably 1 or 2, the same or different, above-mentioned loweralkoxy groups, including, for example, a methoxymethyl group, anethoxymethyl group, a 2-methoxyethyl group, a 2-ethoxyethyl group, a1-methoxy-1-methylethyl group, a 1,2-dimethoxyethyl group, a3-methoxypropyl group.

“Lower alkoxycarbonyl group” means an alkoxycarbonyl group having theabove-mentioned lower alkoxy group, or that is, an alkoxycarbonyl grouphaving from 2 to 7 carbon atoms, including, for example, amethoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group,an isopropoxycarbonyl group, a butoxycarbonyl group, anisobutoxycarbonyl group, a tert-butoxycarbonyl group, apentyloxycarbonyl group.

“Lower alkylsulfonyl group” means a linear or branched alkylsulfonylgroup having from 1 to 6 carbon atoms, including, for example, amethylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, anisopropylsulfonyl group, a butylsulfonyl group, a sec-butylsulfonylgroup, an isobutylsulfonyl group, a tert-butylsulfonyl group, apentylsulfonyl group, an isopentylsulfonyl group, a hexylsulfonyl group,an isohexylsulfonyl group.

“Salts” of the compounds of the invention mean ordinary,pharmaceutically-acceptable salts. For example, when the compounds havea carboxyl group, a hydroxyl group, or an acidic heterocyclic group suchas a tetrazolyl group, then they may form base-addition salts at thecarboxyl group, the hydroxyl group or the acidic heterocyclic group; orwhen the compounds have an amino group or a basic heterocyclic group,then they may form acid-addition salts at the amino group or the basicheterocyclic group.

The base-addition salts include, for example, alkali metal salts such assodium salts, potassium salts; alkaline earth metal salts such ascalcium salts, magnesium salts; ammonium salts; and organic amine saltssuch as trimethylamine salts, triethylamine salts, dicyclohexylaminesalts, ethanolamine salts, diethanolamine salts, triethanolamine salts,procaine salts, N,N′-dibenzylethylenediamine salts.

The acid-addition salts include, for example, inorganic acid salts suchas hydrochlorides, sulfates, nitrates, phosphates, perchlorates;organic-acid salts such as maleates, fumarates, tartrates, citrates,ascorbates, trifluoroacetates; and sulfonates such as methanesulfonates,isethionates, benzenesulfonates, p-toluenesulfonates.

“Esters” of the compounds of the invention means ordinarypharmaceutically-acceptable esters at the carboxyl group, if any, of thecompounds. They include, for example, esters with a lower alkyl groupsuch as a methyl group, an ethyl group, a propyl group, an isopropylgroup, a butyl group, a sec-butyl group, a tert-butyl group, a pentylgroup, an isopentyl group, a neopentyl group, a cyclopropyl group, acyclobutyl group, a cyclopentyl group; esters with an aralkyl group suchas a benzyl group, a phenethyl group; esters with a lower alkenyl groupsuch as an allyl group, a 2-butenyl group; esters with a loweralkoxy-lower alkyl group such as a methoxymethyl group, a 2-methoxyethylgroup, a 2-ethoxyethyl group; esters with a lower alkanoyloxy-loweralkyl group such as an acetoxymethyl group, a pivaloyloxymethyl group, a1-pivaloyloxyethyl group; esters with a lower alkoxycarbonyl-lower alkylgroup such as a methoxycarbonylmethyl group, an isopropoxycarbonylmethylgroup; esters with a carboxy-lower alkyl group such as a carboxymethylgroup; esters with a lower alkoxycarbonyloxy-lower alkyl group such as a1-(ethoxycarbonyloxy)ethyl group, a 1-(cyclohexyloxycarbonyloxy)ethylgroup; esters with a carbamoyloxy-lower alkyl group such as acarbamoyloxymethyl group; esters with a phthalidyl group; esters with a(5-substituted-2-oxo-1,3-dioxol-4-yl)methyl group such as a(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group.

For illustrating the compounds of the invention more concretely,preferred examples of the symbols used in formula (I) and others aredescribed below in more detail.

Ar¹ is an aryl group or a heteroaromatic group, which may have asubstituent selected from a group consisting of a halogen atom, a loweralkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group, alower alkoxy group, a lower alkanoyl group, a hydroxy-lower alkylaminogroup, a carbamoyl group, a hydroxy-lower alkylcarbamoyl group, aheteroaromatic group optionally substituted by a lower alkyl group, anda group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b).

“An aryl group or a heteroaromatic group, which may have a substituentselected from a group consisting of a halogen atom, a lower alkyl group,a halo-lower alkyl group, a hydroxy-lower alkyl group, a lower alkoxygroup, a lower alkanoyl group, a hydroxy-lower alkylamino group, acarbamoyl group, a hydroxy-lower alkylcarbamoyl group, a heteroaromaticgroup optionally substituted by a lower alkyl group, and a group of-Q¹-A¹-Q²-A²(R^(1a))R^(1b)” means the above-mentioned unsubstituted arylgroup or heteroaromatic group, or the above-mentioned aryl group orheteroaromatic group which has a substituent at any substitutableposition thereof and in which the substituent may be one or two or more,preferably 1 or 2, the same or different substituents selected from agroup consisting of a halogen atom, a lower alkyl group, a halo-loweralkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a loweralkanoyl group, a hydroxy-lower alkylamino group, a carbamoyl group, ahydroxy-lower alkylcarbamoyl group, a heteroaromatic group optionallysubstituted by a lower alkyl group, and a group of-Q¹-A¹-Q²-A²(R^(1a))R^(1b).

The halogen atom for the substituent is, for example, preferably afluorine atom, a chlorine atom.

The lower alkyl group for the substituent is, for example, preferably amethyl group, ethyl group.

The halo-lower alkyl group for the substituent is, for example,preferably a fluoromethyl group, a difluoromethyl group, atrifluoromethyl group.

The hydroxy-lower alkyl group for the substituent is, for example,preferably a hydroxymethyl group, a 2-hydroxyethyl group.

The lower alkoxy group for the substituent is, for example, preferably amethoxy group, an ethoxy group.

The lower alkanoyl group for the substituent is, for example, preferablyan acetyl group.

The hydroxy-lower alkylamino group for the substituent is, for example,preferably a hydroxymethylamino group, a 2-hydroxyethylamino group.

The hydroxy-lower alkylcarbamoyl group for the substituent is, forexample, preferably a hydroxymethylcarbamoyl group, a2-hydroxyethylcarbamoyl group.

The “heteroaromatic group optionally substituted by a lower alkyl group”for the substituent means the above-mentioned unsubstitutedheteroaromatic group, or the above-mentioned heteroaromatic group havingone or two or more, preferably one or two, the above-mentioned loweralkyl groups at any substitutable positions therein, and is, forexample, preferably a 4-methyl-1-imidazolyl group, a1-methyl-4-pyrazolyl group.

In the group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b) for the substituent, A¹ is asingle bond, an oxygen atom or a sulfur atom, or is an imino groupoptionally substituted by a lower alkyl group; A² is a nitrogen atom, oris a methine or 1-vinyl-2-ylidene group optionally substituted by ahydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group; Q¹is a single bond, a carbonyl group, or a methylene group optionallysubstituted by a lower alkyl group; Q² is a single bond, or an ethylenegroup optionally substituted by a lower alkyl group; R^(1a) and R^(1b)are independently a hydrogen atom, a lower alkyl group or ahydroxy-lower alkyl group, or together form a lower alkylene groupwherein one or two or more methylene groups constituting the loweralkylene group may be independently replaced by an oxygen atom, a sulfuratom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylenegroup or a group of —N(R^(1c))—, and/or substituted by a hydroxyl groupor a lower alkyl group.

The “imino group optionally substituted by a lower alkyl group” for A²means an unsubstituted imino group, or an imino group substituted by theabove-mentioned lower alkyl group, in which the lower alkyl group forthe substituent is, for example, preferably a methyl group, ethyl group.

The “methine or 1-vinyl-2-ylidene group optionally substituted by ahydroxyl” group, a lower alkyl group or a hydroxy-lower alkyl group” forA² means an unsubstituted methine or 1-vinyl-2-ylidene group, or amethine or 1-vinyl-2-ylidene group having a substituent selected from agroup consisting of a hydroxyl group, a lower alkyl group and ahydroxy-lower alkyl group.

The lower alkyl group for the substituent is, for example, preferably amethyl group, an ethyl group.

The hydroxy-lower alkyl group for the substituent is, for example,preferably a hydroxymethyl group, a 2-hydroxyethyl group.

The substituent is, for example, preferably a hydroxyl group.

The “methylene group optionally substituted by a lower alkyl group” forQ¹ means an unsubstituted methylene group, or a methylene groupsubstituted by the same or different, one or two, above-mentioned loweralkyl groups.

The lower alkyl group for the substituent is preferably a methyl group.

The “ethylene group optionally substituted by a lower alkyl group” forQ² means an unsubstituted ethylene group, or an ethylene groupsubstituted by the same or different, one or two or more, preferably 1or 2, above-mentioned lower alkyl groups at any substitutable positiontherein.

The lower alkyl group for the substituent is preferably a methyl group.

The lower alkyl group for R^(1a) or R^(1b) is, for example, preferably amethyl group, an ethyl group, a propyl group, an isopropyl group.

The hydroxy-lower alkyl group for R^(1a) or R^(1b) is, for example,preferably a hydroxymethyl group, a 2-hydroxyethyl group.

The lower alkylene group that R^(1a) and R^(1b) together form is, forexample, preferably a trimethylene group, a tetramethylene group, apentamethylene group, a hexamethylene group. When “A²” to which theybond is a nitrogen atom, then they form, along with the nitrogen atom, a1-azetidinyl group, a 1-pyrrolidinyl group, a piperidino group, aperhydro-1H-azepin-1-yl group. When “A²” is a methine group, then theyform, along with the methine group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group, a cycloheptyl group. When “A²” is a1-vinyl-2-ylidene group, then they form, along with the1-vinyl-2-ylidene group, a 1-cyclopentenyl group, a 1-cyclohexenylgroup, a 1-cycloheptenyl group, a 1-cyclooctenyl group. Above all, morepreferred are a 1-pyrrolidinyl group, a piperidino group, aperhydro-1H-azepin-1-yl group, a cyclobutyl group, a cyclohexyl group, a1-cyclohexenyl group.

One or two or more methylene groups constituting the lower alkylenegroup may be independently replaced by an oxygen atom, a sulfur atom, asulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group ora group of —N(R^(1c))—, and/or substituted by a hydroxyl group or alower alkyl group. Examples of the replaced or substituted groups arepreferably selected from the following formula (aa1):

Above all, examples of the groups are more preferably selected from thefollowing formula (aa1′):

R^(1c) in the group of —N(R^(1c))— is a hydrogen atom, a lower alkenylgroup or a group of -Q³-A³(R^(1d))R^(1e).

The lower alkenyl group for R^(1c) is, for example, preferably a vinylgroup, an allyl group.

In the group of -Q³-A³(R^(1d))R^(1e) for R^(1c), A³ is a nitrogen atom,or is a methine or 1-vinyl-2-ylidene group optionally substituted by ahydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group; Q³is a single bond or a lower alkylene group, wherein one or two or moremethylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom, a sulfur atom, a carbonylgroup, a sulfinyl group or a sulfonyl group, and/or substituted by ahalogen atom, a cyano group, a hydroxyl group or a lower alkyl group;R^(1d) and R^(1e) are independently a hydrogen atom, a halogen atom, acyano group, a hydroxyl group, a lower alkyl group or a hydroxy-loweralkyl group, or together form a lower alkylene group wherein one or twoor more methylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom, a sulfur atom, a sulfinylgroup, a sulfonyl group, a carbonyl group, a vinylene group or a groupof —N(R^(1f))—, and/or substituted by a hydroxyl group or a lower alkylgroup.

The “methine or 1-vinyl-2-ylidene group optionally substituted by ahydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group” forA³ means an unsubstituted methine or 1-vinyl-2-ylidene group, or amethine or 1-vinyl-2-ylidene group having a substituent selected from agroup consisting of a hydroxyl group, a lower alkyl group and ahydroxy-lower alkyl group.

The lower alkyl group for the substituent is, for example, preferably amethyl group, an ethyl group.

The hydroxy-lower alkyl group for the substituent is, for example,preferably a hydroxymethyl group, a 2-hydroxyethyl group, a2-hydroxypropyl group, a 2-methyl-2-hydroxypropyl group.

The substituent is preferably a hydroxyl group, a lower alkyl group.

The lower alkylene group for Q³ is, for example, preferably a methylenegroup, an ethylene group, a trimethylene group.

One or two or more methylene groups constituting the lower alkylenegroup for Q³ may be independently replaced by an oxygen atom, a sulfuratom, a carbonyl group, a sulfinyl group or a sulfonyl group, and/orsubstituted by a halogen atom, a cyano group, a hydroxyl group or alower alkyl group. Examples of the replaced or substituted groups arepreferably selected from the following formula (aa2):

The halogen atom for R^(1d) or R^(1e) is, for example, preferably afluorine atom, a chlorine atom.

The lower alkyl for R^(1d) or R^(1e) is, for example, preferably amethyl group, an ethyl group.

The hydroxy-lower alkyl group for R^(1d) or R^(1e) is, for example,preferably a hydroxymethyl group, a 2-hydroxyethyl group.

The lower alkylene group which for R^(1d) and R^(1e) together form is,for example, preferably an ethylene group, a trimethylene group, atetramethylene group. When “A³” to which they bond is a nitrogen atom,then they form along with the nitrogen atom, a 1-aziridinyl group, a1-azetidinyl group, a 1-pyrrolidinyl group; when “A³” is a methinegroup, they form along with the methine group, a cyclopropyl group, acyclobutyl group, a cyclopentyl group; when “A³” is a 1-vinyl-2-ylidenegroup, then they form along with the 1-vinyl-2-ylidene group, a1-cyclobutenyl group, a 1-cyclopentenyl group, a 1-cyclohexenyl group.Above all, more preferred are a cyclopropyl group, a cyclobutyl group, acyclopentyl group.

One or two or more methylene groups constituting the above-mentionedlower alkylene group may be independently replaced by an oxygen atom, asulfur atom, a sulfinyl group or a sulfonyl group, a carbonyl group, avinylene group or a group of —N(R^(1f))—, and/or substituted by ahydroxyl group or a lower alkyl group. Examples of the replaced orsubstituted groups are preferably selected from the following formula(aa3):

R^(1f) in the group of —N(R^(1f))— is a hydrogen atom, a lower alkylgroup, a halo-lower alkyl group, a lower alkenyl group or a loweralkanoyl group.

The lower alkyl group for R^(1f) is, for example, preferably a methylgroup, an ethyl group.

The halo-lower alkyl group for R^(1f) is, for example, preferably afluoromethyl group, a difluoromethyl group.

The lower alkenyl group for R^(1f) is, for example, preferably an allylgroup.

The lower alkanoyl group for R^(1f) is, for example, preferably anacetyl group.

Preferred embodiments of the group of -Q³-A³(R^(1d))R^(1e) are, forexample, as follows:

(i) A³ is a methine group optionally substituted by a hydroxyl group ora lower alkyl group, Q³ is a single bond, and R^(1d) and R^(1e) areindependently a hydrogen atom or a lower alkyl group,

(ii) A³ is a methine group, Q³ is a single bond or a lower alkylenegroup, and R^(1d) and R^(1e) together form a lower alkylene groupwherein one methylene group constituting the lower alkylene group may bereplaced by a group of —N(R^(1f))—,

(iii) A³ is a methine group optionally substituted by a hydroxyl groupor a lower alkyl group, Q³ is a lower alkylene group wherein one or twomethylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom, a carbonyl group or a sulfonylgroup, and/or substituted by a hydroxyl group, and R^(1d) and R^(1c) areindependently a hydrogen atom, a halogen atom, a cyano group or a loweralkyl group;

(iv) A³ is a nitrogen atom, Q³ is a lower alkylene group wherein onemethylene group constituting the lower alkylene group is replaced by acarbonyl group, and R^(1d) and R^(1e) are independently a hydrogen atomor a lower alkyl group; more preferably above (i).

More concretely, the group of -Q³-A³(R^(1d))R^(1e) is, for example,preferably a methyl group, an ethyl group, a propyl group, an isopropylgroup, a tert-butyl group, a hydroxymethyl group, a1-hydroxy-1-methylethyl group, a cyclopropyl group, a cyclobutyl group,a cyclopropylmethyl group, a 1-acetyl-3-azetidinyl group, a cyclopentylgroup, a 2-hydroxycyclopentyl group, a 2-hydroxyethyl group, a2-cyanoethyl group, a 2-methoxyethyl group, a 2-ethoxyethyl group, a2-hydroxy-2-methylpropyl group, a 3-fluoro-2-hydroxypropyl group, anacetyl group, a propionyl group, a 2-methoxyacetyl group, atert-butoxycarbonyl group, a methylsulfonyl group, a2-(methylsulfonyl)ethyl group, a dimethylcarbamoyl group, adimethylcarbamoylmethyl group, a 2-(dimethylamino)acetyl group; morepreferably a methyl group, an ethyl group, a tert-butyl group, a2-hydroxyethyl group, a 2-methoxyethyl group, an acetyl group; morepreferably a methyl group.

R^(1c) is preferably a hydrogen atom or a group of -Q³-A³(R^(1d))R^(1e),more preferably a group of -Q³-A³(R^(1d))R^(1e).

Preferred embodiments of the group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b) are,for example, as follows:

(i) A¹, Q¹ and Q² are a single bond, A² is a nitrogen atom, and R^(1a)and R^(1b) together form a lower alkylene group wherein one or twomethylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom, a sulfonyl group, a carbonylgroup or a group of —N(R^(1c))—, and/or substituted by a hydroxyl group;

(ii) A¹, Q¹ and Q² are a single bond, A² is a methine or1-vinyl-2-ylidene group optionally substituted by a hydroxyl group, andR^(1a) and R^(1b) together form a lower alkylene group wherein onemethylene group constituting the lower alkylene group is replaced by agroup of —N(R^(1c))—;

(iii) A¹ is an oxygen atom, A² is a methine group, Q¹ and Q² are asingle bond, and R^(1a) and R^(1b) together form a lower alkylene groupwherein one methylene group constituting the lower alkylene group isreplaced by a group of —N(R^(1c))—;

(iv) A¹ is an oxygen atom, A² is a nitrogen atom, Q¹ is a single bond,Q² is an ethylene group, and R^(1a) and R^(1b) are independently a loweralkyl group; or

(v) A¹ and Q² are a single bond, A² is a nitrogen atom, Q¹ is amethylene group, and R^(1a) and R^(1b) are independently a lower alkylgroup.

Above all, cases (i) or (ii) are more preferrably and examples of thegroups are more preferably selected from the following formula (aa1′):

More concretely, the group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b) is preferably a1-piperazinyl group; a 4-methyl-1-piperazinyl group, a4-ethyl-1-piperazinyl group, a 4-propyl-1-piperazinyl group, a4-isopropyl-1-piperazinyl group, a 4-tert-butyl-1-piperazinyl group, a4-hydroxymethyl-1-piperazinyl group, a4-(1-hydroxy-1-methylethyl)-1-piperazinyl group, a4-cyclopropyl-1-piperazinyl group, a 4-cyclobutyl-1-piperazinyl group, a4-cyclopropylmethyl-1-piperazinyl group, a4-(1-acetyl-3-azetidinyl)-1-piperazinyl group, a4-cyclopentyl-1-piperazinyl group, a4-(2-hydroxycyclopentyl)-1-piperazinyl group, a4-(2-hydroxyethyl)-1-piperazinyl group, a 4-(2-cyanoethyl)-1-piperazinylgroup, a 4-(2-methoxyethyl)-1-piperazinyl group, a4-(2-ethoxyethyl)-1-piperazinyl group, a4-(2-hydroxy-2-methylpropyl)-1-piperazinyl group, a4-(3-fluoro-2-hydroxypropyl)-1-piperazinyl group, a4-acetyl-1-piperazinyl group, a 4-propionyl-1-piperazinyl group, a4-(2-methoxyacetyl)-1-piperazinyl group, a4-tert-butoxycarbonyl-1-piperazinyl group, a4-methylsulfonyl-1-piperazinyl group, a4-(2-(methylsulfonyl)ethyl)-1-piperazinyl group, a 4-(dimethylcarbamoyl)group, a 4-(dimethylcarbamoylmethyl)-1-piperazinyl group, a4-(2-(dimethylamino)acetyl)-1-piperazinyl group, a4-methyl-3-oxo-1-piperazinyl group, a piperidino group, a4-hydroxypiperidino group, a morpholino group, a thiomorpholino group, a1,1-dioxidothiomorpholino group, a perhydro-1H-azepin-1-yl group, aperhydro-1H-1,4-diazepin-1-yl group, a4-methyl-perhydro-1H-1,4-diazepin-1-yl group, a5-oxo-perhydro-1H-1,4-diazepin-1-yl group, a4-methyl-5-oxo-perhydro-1H-1,4-diazepin-1-yl group, a 3-azetidinylgroup, a 4-piperidyl group, a 1-methyl-4-piperidyl group, a1-ethyl-4-piperidyl group, a 1-(2-hydroxyethyl)-4-piperidyl group, a1-(2-methylsulfonylethyl)-4-piperidyl group, a 4-hydroxy-4-piperidylgroup, a 4-hydroxy-1-methyl-4-piperidyl group, a1-tert-butoxycarbonyl-4-hydroxy-4-piperidyl group, a1,2,3,6-tetrahydro-4-pyridyl group, a 3-azetidinyloxy group, a1-methyl-3-azetidinyloxy group, a 1-ethyl-3-azetidinyloxy group, a1-propyl-3-azetidinyloxy group, a 1-isopropyl-3-azetidinyloxy group, a1-(2-hydroxyethyl)-3-azetidinyloxy group, a 4-piperidyloxy group, a1-methyl-4-piperidyloxy group, a 1-ethyl-4-piperidyloxy group, a1-cyclobutyl-4-piperidyloxy group, a 2-dimethylaminoethoxy group, adimethylaminomethyl group, a diethylaminomethyl group, amethylpropylaminomethyl group, an isopropylmethylaminomethyl group; morepreferably a 1-piperazinyl group, a 4-methyl-1-piperazinyl group, a4-ethyl-1-piperazinyl group, a 4-isopropyl-1-piperazinyl group, a4-tert-butyl-1-piperazinyl group, a 4-cyclopropyl-1-piperazinyl group, a4-cyclobutyl-1-piperazinyl group, a 4-cyclopropylmethyl-1-piperazinylgroup, a 4-(2-hydroxyethyl)-1-piperazinyl group, a4-(2-methoxyethyl)-1-piperazinyl group, a4-(2-methoxyacetyl)-1-piperazinyl group, a 4-acetyl-1-piperazinyl group,a 4-methylsulfonyl-1-piperazinyl group, a 4-methyl-3-oxo-1-piperazinylgroup, a 4-hydroxypiperidino group, a morpholino group, a1,1-dioxidothiomorpholino group, a4-methyl-5-oxo-perhydro-1H-1,4-diazepin-1-yl group, a 4-piperidyl group,a 1-methyl-4-piperidyl group, a 1-(2-hydroxyethyl)-4-piperidyl group, a4-hydroxy-1-methyl-4-piperidyl group, a 1,2,3,6-tetrahydro-4-pyridylgroup, a 1-ethyl-3-azetidinyloxy group, a 1-isopropyl-3-azetidinyloxygroup, a 1-(2-hydroxyethyl)-3-azetidinyloxy group, even more preferablya 4-methyl-1-piperazinyl group, a 4-ethyl-1-piperazinyl group, a4-(2-hydroxyethyl)-1-piperazinyl group, a 4-acetyl-1-piperazinyl group,a 1-methyl-4-piperidyl group.

The substituent for Ar¹ is, for example, preferably a lower alkyl group,a hydroxy-lower alkyl group, a lower alkoxy group, a lower alkanoylgroup, a heteroaromatic group optionally substituted by a lower alkylgroup, or a group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b).

The “aryl group” itself of the aryl group optionally having theabove-mentioned substituent for Ar¹ is, for example, preferably a phenylgroup. The “heteroaromatic group” itself of the heteroaromatic groupoptionally having the above-mentioned substituent for Ar¹ is, forexample, preferably a pyrazolyl group, a pyridyl group.

Accordingly, Ar¹ is, for example, preferably a phenyl, pyrazolyl orpyridyl group optionally substituted by a lower alkyl group, ahydroxy-lower alkyl group, a lower alkoxy group, a lower alkanoyl group,a heteroaromatic group optionally substituted by a lower alkyl group, ora group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b); more preferably a phenyl groupsubstituted by one -Q¹-A¹-Q²-A²(R^(1a))R^(1b), or a phenyl groupsubstituted by one group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b) and additionallyby a lower alkyl group or a hydroxy-lower alkyl group.

More concretely, Ar¹ is preferably a phenyl group, a4-hydroxymethyl-3-methylphenyl group, a 4-isopropyloxyphenyl group, a4-acetylphenyl group, a 3,5-dimethyl-4-(2-dimethylaminoethoxy)phenylgroup, a 4-(1-methyl-1H-pyrazol-4-yl)phenyl group, a4-(1-piperazinyl)phenyl group, a 3-methyl-4-(1-piperazinyl)phenyl group,a 3-hydroxymethyl-4-(1-piperazinyl)phenyl group, a4-(4-methyl-1-piperazinyl)phenyl group, a3-methyl-4-(4-methyl-1-piperazinyl)phenyl group, a3-hydroxymethyl-4-(4-methyl-1-piperazinyl)phenyl group, a4-(4-ethyl-1-piperazinyl)phenyl group, a4-(4-ethyl-1-piperazinyl)-3-hydroxymethylphenyl group, a4-(4-isopropyl-1-piperazinyl)phenyl group, a3-methyl-4-(4-isopropyl-1-piperazinyl)phenyl group, a4-(4-tert-butyl-1-piperazinyl)phenyl group, a4-(4-cyclopropyl-1-piperazinyl)phenyl group, a4-(4-cyclopropyl-1-piperazinyl)-3-methylphenyl group, a4-(4-cyclopropyl-1-piperazinyl)-3-hydroxymethylphenyl group, a4-(4-cyclobutyl-1-piperazinyl)phenyl group, a4-(4-cyclobutyl-1-piperazinyl)-3-methylphenyl group, a4-(4-cyclopropylmethyl-1-piperazinyl)phenyl group, a4-(4-cyclopropylmethyl-1-piperazinyl)-3-methylphenyl group, a4-(4-(2-hydroxyethyl)-1-piperazinyl)phenyl group, a4-(4-(2-hydroxyethyl)-1-piperazinyl)-3-methylphenyl group, a4-(4-(2-methoxyethyl)-1-piperazinyl)phenyl group, a4-(4-acetyl-1-piperazinyl)phenyl group, a4-(4-(2-methoxyacetyl)-1-piperazinyl)phenyl group, a3-hydroxymethyl-4-(4-(2-methoxyacetyl)-1-piperazinyl)phenyl group, a4-(4-methylsulfonyl-1-piperazinyl)phenyl group, a3-methyl-4-(4-methylsulfonyl-1-piperazinyl)phenyl group, a4-(4-methyl-3-oxo-1-piperazinyl)phenyl group, a3-methyl-4-(4-methyl-3-oxo-1-piperazinyl)phenyl group, a4-(4-hydroxypiperidino)phenyl group, a4-(4-hydroxypiperidino)-3-methylphenyl group, a4-(4-hydroxypiperidino)-3-hydroxymethylphenyl group, a4-morpholinophenyl group, a 3-methyl-4-morpholinophenyl group, a3-hydroxymethyl-4-morpholinophenyl group,4-(1,1-dioxidothiomorpholino)phenyl group, a3-methyl-4-(1,1-dioxidothiomorpholino)phenyl group, a47(4-methyl-5-oxo-perhydro-1H-1,4-diazepin-1-yl)phenyl group, a4-(4-piperidyl)phenyl group, a 4-(1-methyl-4-piperidyl)phenyl group, a3-methyl-4-(4-piperidyl)phenyl group, a 4-(4-hydroxy-4-piperidyl)phenylgroup, a 4-(4-hydroxy-1-methyl-4-piperidyl)phenyl group, a4-(1-(2-hydroxyethyl)-4-piperidyl)phenyl group, a4-(1-(2-hydroxyethyl)-4-piperidyl)-3-methylphenyl group, a4-(1-tert-butoxycarbonyl-4-hydroxy-4-piperidyl)phenyl group, a4-(1,2,3,6-tetrahydro-4-pyridyl)phenyl group, a3-methyl-4-(1,2,3,6-tetrahydro-4-pyridyl)phenyl group, a4-(3-azetidinyloxy)phenyl group, a 4-(3-azetidnyloxy)-3-methylphenylgroup, a 4-(1-ethyl-3-azetidinyloxy)phenyl group, a4-(1-ethyl-3-azetidinyloxy)-3-methylphenyl group, a4-(1-isopropyl-3-azetidinyloxy)phenyl group, a4-(1-isopropyl-3-azetidinyloxy)-3-methylphenyl group, a4-(1-(2-hydroxyethyl)-3-azetidinyloxy)phenyl group, a4-(1-(2-hydroxyethyl)-3-azetidinyloxy)-3-methylphenyl group; morepreferably a 4-acetylphenyl group, a3,5-dimethyl-4-(2-dimethylaminoethoxy)phenyl group, a3-methyl-4-(1-piperazinyl)phenyl group, a4-(4-methyl-1-piperazinyl)phenyl group, a3-methyl-4-(4-methyl-1-piperazinyl)phenyl group, a3-hydroxymethyl-4-(4-methyl-1-piperazinyl)phenyl group, a4-(4-ethyl-1-piperazinyl)phenyl group, a4-(4-isopropyl-1-piperazinyl)phenyl group, a4-(4-tert-butyl-1-piperazinyl)phenyl group, a4-(4-cyclobutyl-1-piperazinyl)-3-methylphenyl group, a4-(4-cyclopropylmethyl-1-piperazinyl)-3-methylphenyl group, a4-(4-(2-hydroxyethyl)-1-piperazinyl)phenyl group, a4-(4-(2-hydroxyethyl)-1-piperazinyl)-3-methylphenyl group, a4-(4-(2-methoxyethyl)-1-piperazinyl)phenyl group, a4-(4-acetyl-1-piperazinyl)phenyl group, a3-methyl-4-(4-methylsulfonyl-1-piperazinyl)phenyl group, a4-(4-methyl-3-oxo-1-piperazinyl)phenyl group, a3-methyl-4-(4-methyl-3-oxo-1-piperazinyl)phenyl group, a4-(4-hydroxypiperidino)-3-methylphenyl group, a4-(4-hydroxypiperidino)-3-hydroxymethylphenyl group, a3-methyl-4-morpholinophenyl group, a 3-hydroxymethyl-4-morpholinophenylgroup, a 3-methyl-4-(1,1-dioxidothiomorpholino)phenyl group, a4-(4-methyl-5-oxo-perhydro-1H-1,4-diazepin-1-yl)phenyl group, a4-(4-piperidyl)phenyl group, a 4-(1-methyl-4-piperidyl)phenyl group, a4-(4-hydroxy-1-methyl-4-piperidyl)phenyl group, a4-(1-(2-hydroxyethyl)-4-piperidyl)-3-methylphenyl group, a4-(1-tert-butoxycarbonyl-4-hydroxy-4-piperidyl)phenyl group, a3-methyl-4-(1,2,3,6-tetrahydro-4-pyridyl)phenyl group, a4-(1-ethyl-3-azetidinyloxy)-3-methylphenyl group, a4-(1-isopropyl-3-azetidinyloxy)-3-methylphenyl group; even morepreferably a 4-(4-methyl-1-piperazinyl)phenyl group, a3-methyl-4-(4-methyl-1-piperazinyl)phenyl group, a3-hydroxymethyl-4-(4-methyl-1-piperazinyl)phenyl group, a4-(4-ethyl-1-piperazinyl)phenyl group, a4-(4-(2-hydroxyethyl)-1-piperazinyl)phenyl group, a4-(4-acetyl-1-piperazinyl)phenyl group, a 4-(1-methyl-4-piperidyl)phenylgroup.

R¹ is a lower alkyl group, a lower alkenyl group, a lower alkynyl groupor a cyclo-lower alkyl group optionally substituted by a halogen atom,or is an aryl group, an aralkyl group or a heteroaromatic groupoptionally having a substituent selected from a group consisting of ahalogen atom, a cyano group, an amino group and a lower alkyl group.

The “alkyl group, the lower alkenyl group, the lower alkynyl group orthe cyclo-lower alkyl group optionally substituted by a halogen atom”for R¹ means the above-mentioned unsubstituted lower alkyl, loweralkenyl, lower alkynyl or cyclo-lower alkyl group, or theabove-mentioned lower alkyl, lower alkenyl, lower alkynyl or cyclo-loweralkyl group substituted by the above-mentioned halogen atom. The groupmay have the same or different, one or two or more, preferably from 1 to3 halogen atoms at any substitutable position therein.

The halogen atom for the substituent is, for example, preferably afluorine atom, a chlorine atom.

The “lower alkyl group optionally substituted by a halogen atom” for R¹is, for example, preferably a methyl group, an ethyl group, a propylgroup, an isopropyl group, a 2,2-difluoroethyl group, a2,2,2-trifluoroethyl group, more preferably an ethyl group or anisopropyl group.

The “lower alkenyl group optionally substituted by a halogen atom” forR¹ is, for example, preferably an allyl group, a 2-methyl-2-propenylgroup, a 3-methyl-2-butenyl group, especially preferably an allyl group.

The “lower alkynyl group optionally substituted by a halogen atom” forR¹ is, for example, preferably a 2-propynyl group.

The “cyclo-lower alkyl group optionally substituted by a halogen atom”for R¹ is, for example, preferably a cyclopropyl group, a cyclobutylgroup.

The “aryl group, the aralkyl group or the heteroaromatic groupoptionally having a substituent selected from a group consisting of ahalogen atom, a cyano group, an amino group and a lower alkyl group” forR¹ means the above-mentioned unsubstituted aryl group, aralkyl group orheteroaromatic group, or the above-mentioned aryl group, aralkyl groupor heteroaromatic group having a substituent at any substitutableposition therein, for which the same or different, one or two or more,preferably 1 or 2 substituents may be selected from the group consistingof a halogen atom, a cyano group, an amino group and a lower alkylgroup.

The halogen atom for the substituent is, for example, preferably afluorine atom, a chlorine atom.

The lower alkyl group for the substituent is, for example, preferably amethyl group, an ethyl group.

The substituent is preferably a halogen atom, a cyano group, an aminogroup, more preferably a halogen atom.

The aryl group optionally having a substituent for R¹ is, for example,preferably a phenyl group, a 1-naphthyl group, a 2-chlorophenyl group, a2,6-dichlorophenyl group, a 2-cyanophenyl group, a2-chloro-6-cyanophenyl group.

The heteroaromatic group optionally having a substituent for R¹ is, forexample, preferably a 2-pyridyl group, a 3-chloro-2-pyridyl group.

The aralkyl group optionally having a substituent for R¹ is, forexample, preferably a benzyl group, an α-methylbenzyl group.

Preferred embodiments of R¹ are, for example, a lower alkyl groupoptionally substituted by a halogen atom, more concretely, an ethylgroup and an isopropyl group etc.

Another preferred embodiments of R¹ are, for example, a lower alkenylgroup optionally substituted by a halogen atom, more concretely, anallyl group, a 2-methyl-2-propenyl group, a 3-methyl-2-butenyl group;more preferably an allyl group.

Another preferred embodiments of R¹ are, for example, a lower alkynylgroup optionally substituted by a halogen atom, more concretely, a2-propynyl group.

Another preferred embodiments of R¹ are, for example, a phenyl or benzylgroup optionally having a substituent selected from a group consistingof a halogen atom, a cyano group, an amino group and a lower alkylgroup, more concretely, a 2-chlorophenyl group, a 2,6-dichlorophenylgroup, a 2-cyanophenyl group, a 2-chloro-6-cyanophenyl group, a benzylgroup, an α-methylbenzyl group; more preferably a 2-chlorophenyl group.

Especially a lower alkenyl group such as an allyl group etc. ispreferred for R¹.

R² is a hydrogen atom, a lower alkyl group, a lower alkenyl group or alower alkynyl group, or is an aryl group, an aralkyl group or aheteroaromatic group optionally having a substituent selected from agroup consisting of a halogen atom, a cyano group, a nitro group, acarboxyl group, a group of -Q⁴-A⁴(R^(1g))R^(1h) and a group of-Q⁵-Ar^(a), wherein one or two or more methylene groups constituting thelower alkyl group, the lower alkenyl group or the lower alkynyl groupmay be independently replaced by an oxygen atom, a sulfur atom, asulfinyl group, a sulfonyl group, a carbonyl group or a group of—N(R^(1j))—, and/or substituted by a halogen atom.

The lower alkyl group for R² is, for example, preferably a methyl group,an ethyl group.

The lower alkenyl group for R² is, for example, preferably an allylgroup.

The lower alkynyl group for R² is, for example, preferably a 2-propynylgroup.

One or two or more methylene groups constituting the lower alkyl group,the lower alkenyl group or the lower alkynyl group for R² may beindependently replaced by an oxygen atom, a sulfur atom, a sulfinylgroup, a sulfonyl group, a carbonyl group or a group of —N(R^(1j))—,and/or substituted by a halogen atom. The replaced or substituted groupis, for example, preferably a methoxymethyl group, amethylsuflonylmethyl group, an acetyl group or a group of a formula(bb1):

R^(1j) is a hydrogen atom or a lower alkyl group, for example,preferably a hydrogen atom or a methyl group.

The “aryl group, the aralkyl group or the heteroaromatic groupoptionally having a substituent selected from a group consisting of ahalogen atom, a cyano group, a nitro group, a carboxyl group, a group of-Q⁴-A⁴(R^(1g))R^(1h) and a group of -Q⁵-Ar^(a)” for R² means theabove-mentioned unsubstituted aryl, aralkyl or heteroaromatic group, orthe above-mentioned aryl, aralkyl or heteroaromatic group having asubstituent at any substitutable position therein, for which the same ordifferent, one or two or more, preferably 1 or 2 substituents may beselected from a group consisting of a halogen atom, a cyano group, anitro group, a carboxyl group, a group of -Q⁴-A⁴(R^(1g))R^(1h) and agroup of -Q⁵-Ar^(a).

The halogen atom for the substituent is, for example, preferably afluorine atom, a chlorine atom, a bromine atom.

In the group of for the substituent, A⁴ is a nitrogen atom, or is a-Q⁴-A⁴(R^(1g))R^(1h) methine group optionally substituted by a halogenatom, a hydroxyl group, a lower alkyl group or a hydroxy-lower alkylgroup; Q⁴ is a single bond or a lower alkylene group, wherein one or twoor more methylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom or a carbonyl group, and/orsubstituted by a lower alkyl group; R^(1g) and R^(1h) are independentlya hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, alower alkyl group, a lower alkoxy-lower alkyl group, a lower alkanoylgroup, a lower alkoxycarbonyl group or a lower alkylsulfonyl group, ortogether form a lower alkylene group, wherein one or two or moremethylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom, a sulfur atom, a sulfinylgroup, a sulfonyl group, a carbonyl group or a group of —N(R^(1i))—,and/or substituted by a halogen atom or a lower alkyl group.

The “methine group optionally substituted by a halogen atom, a hydroxylgroup, a lower alkyl group or a hydroxy-lower alkyl group” for A⁴ meansan unsubstituted methine group, or a methine group having a substituentselected from a group consisting of a halogen atom, a hydroxyl group, alower alkyl group and a hydroxy-lower alkyl group.

The halogen atom for the substituent is, for example, preferably afluorine atom, a chlorine atom.

The lower alkyl group for the substituent is, for example, preferably amethyl group, an ethyl group.

The hydroxy-lower alkyl group for the substituent is, for example,preferably a hydroxymethyl group, a 2-hydroxyethyl group.

The substituent is, for example, preferably a halogen atom, a hydroxylgroup, a lower alkyl group.

The lower alkylene group for Q⁴ is, for example, preferably a methylenegroup, an ethylene group, a trimethylene group.

One or two or more methylene groups constituting the lower alkylenegroup for Q⁴ may be independently replaced by an oxygen atom or acarbonyl group, and/or substituted by a lower alkyl group. The replacedor substituted group is, for example, preferably selected from thefollowing formula (bb2):

The halogen atom for R^(1g) or R^(1h) is, for example, preferably afluorine atom, a chlorine atom.

The lower alkyl group for R^(1g) or R^(1h) is, for example, preferably amethyl group, an ethyl group, an isopropyl group.

The lower alkoxy-lower alkyl group for R^(1g) or R^(1h) is, for example,preferably a methoxymethyl group, a 2-methoxyethyl group, a3-methoxypropyl group.

The lower alkanoyl group for R^(1g) or R^(1h) is, for example,preferably an acetyl group.

The lower alkoxycarbonyl group for R^(1g) or R^(1h) is, for example,preferably a methoxycarbonyl group, a tert-butoxycarbonyl group.

The lower alkylsulfonyl group for R^(1g) or R^(1h) is, for example,preferably a methylsulfonyl group, an ethylsulfonyl group.

The lower alkylene group that R^(1g) and R^(1h) together form is, forexample, preferably an ethylene group, a trimethylene group, atetramethylene group, a pentamethylene group. When “A⁴” to which theybond is a nitrogen atom, then they form along with the nitrogen atom, a1-aziridinyl group, a 1-azetidinyl group, a 1-pyrrolidinyl group, apiperidino group; when “A⁴” is a methine group, they form along with themethine group, a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group. Above all, more preferred are a1-pyrrolidinyl group, a piperidino group, a cyclobutyl group, acyclohexyl group.

One or two or more methylene groups constituting the above-mentionedlower alkylene group may be independently replaced by an oxygen atom, asulfur atom, a sulfinyl group or a sulfonyl group, a carbonyl group or agroup of —N(R^(1i))—, and/or substituted by a halogen atom or a loweralkyl group. Examples of the replaced or substituted groups arepreferably selected from the following formula (bb3):

Above all, examples of the groups are more preferably selected from thefollowing formula (bb3′):

R^(1i) in the group of —N(R^(1i))— is a hydrogen atom, a lower alkylgroup or a halo-lower alkyl group.

The lower alkyl group for R^(1i) is, for example, preferably a methylgroup, an ethyl group.

The halo-lower alkyl group for R^(1i) is, for example, preferably afluoromethyl group, a difluoromethyl group.

Preferred embodiments of the group of -Q⁴-A⁴(R^(1g))R^(1h) are, forexample, as follows:

(i) A⁴ is a nitrogen atom, Q⁴ is a single bond or a methylene groupoptionally substituted by a lower alkyl group, and R^(1g) and R^(1h) areindependently a hydrogen atom, a lower alkyl group, a lower alkanoylgroup, a lower alkoxycarbonyl group or a lower alkylsulfonyl group;

(ii) A⁴ is a nitrogen atom or is a methine group optionally substitutedby a halogen atom, a hydroxyl group, a lower alkyl group or ahydroxy-lower alkyl group, Q⁴ is a carbonyl group, and R^(1g) and R^(1h)are independently a hydrogen atom or a lower alkyl group;

(iii) A⁴ is a methine group optionally substituted by a halogen atom, ahydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group, Q⁴is a single bond or a methylene group optionally replaced by an oxygenatom, and R^(1g) and R^(1h) are independently a hydrogen atom, a halogenatom, a hydroxyl group, a lower alkyl group or a lower alkoxycarbonylgroup;

(iv) A⁴ is a methine group optionally substituted by a halogen atom, ahydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group, Q⁴is an ethylene group, in which one or two methylene groups constitutingthe ethylene group may be independently replaced by an oxygen atom or acarbonyl group, and R^(1g) and R^(1h) are independently a hydrogen atom,a hydroxyl group or a lower alkyl group;

(v) A⁴ is a methine group optionally substituted by a halogen atom, ahydroxyl group, a lower alkyl group or a hydroxy-lower alkyl group, Q⁴is a single bond, and R^(1g) and R^(1h) together form a lower alkylenegroup, in which one or two or more methylene groups constituting thelower alkylene group may be independently replaced by an oxygen atom ora group of —N(R^(1i))—; or

(vi) A⁴ is a nitrogen atom, Q⁴ is a single bond, and R^(1g) and R^(1h)together form a lower alkylene group, in which one or two or moremethylene groups constituting the lower alkylene group may beindependently replaced by a carbonyl group or a group of —N(R^(1i))—;more preferably above (iii).

More concretely, the group of -Q⁴-A⁴(R^(1g))R^(1h) is, for example,preferably an amino group, a methylaminomethyl group, adimethylaminomethyl group, an isopropylmethylamino group, a1-amino-1-methylethyl group, a methylsulfonylamino group, anN-methyl-N-acetylaminomethyl group, anN-methyl-N-methoxycarbonylaminomethyl group, anN-methyl-N-methylsulfonylaminomethyl group, a carbamoyl group, amethylcarbamoyl group, a dimethylcarbamoyl group, an acetyl group, amethyl group, a trifluoromethyl group, a 1-fluoro-1-methylethyl group, ahydroxymethyl group, a 1-hydroxyethyl group, a 1-hydroxy-1-methylethylgroup, a 2-hydroxy-1,1-dimethylethyl group, a 2-hydroxy-2-methylpropylgroup, a 2-hydroxy-1,1-dimethylpropyl group, a1-methoxycarbonyl-1-methylethyl group, a methoxy group, a2-hydroxyethoxy group, a methoxycarbonyl group, a tert-butoxycarbonylgroup, a 1-hydroxycyclobutyl group, a 4-hydroxy-tetrahydropyran-4-ylgroup, a 2-oxo-1-pyrrolidinyl group, or a3-methyl-2-oxoimidazolidin-1-yl group; more preferably an amino group, adimethylaminomethyl group, a methylsulfonylamino group, anN-methyl-N-methylsulfonylaminomethyl group, a carbamoyl group, adimethylcarbamoyl group, a methyl group, a 1-fluoro-1-methylethyl group,a hydroxymethyl group, a 1-hydroxy-1-methylethyl group, a2-hydroxy-1,1-dimethylethyl group, a 2-hydroxy-2-methylpropyl group, a2-hydroxy-1,1-dimethylpropyl group, a methoxy group, a 2-hydroxyethoxygroup, a 1-hydroxycyclobutyl group, a 2-oxo-1-pyrrolidinyl group, or a3-methyl-2-oxoimidazolidin-1-yl group, even more preferably a1-hydroxy-1-methylethyl group etc.

In the group of -Q⁵-Ar^(a) for the substituent for the aryl group, thearalkyl group or the heteroaromatic group for R², Ar^(a) is an arylgroup or a heteroaromatic group, which may have a substituent selectedfrom a group consisting of a halogen atom, a lower alkyl group, ahalo-lower alkyl group, a hydroxy-lower alkyl group and a lower alkoxygroup; Q⁵ is a single bond, an oxygen atom, a sulfur atom, a carbonylgroup or a lower alkylene group, wherein one or two or more methylenegroups constituting the lower alkylene group may be independentlyreplaced by an oxygen atom, a sulfur atom or a carbonyl group, and/orsubstituted by a halogen atom or a lower alkyl group.

The “aryl group or the heteroaromatic group, which may have asubstituent selected from a group consisting of a halogen atom, a loweralkyl group, a halo-lower alkyl group, a hydroxy-lower alkyl group and alower alkoxy group” for Ar^(a) means the above-mentioned unsubstitutedaryl or heteroaromatic group, or the above-mentioned aryl orheteroaromatic group having a substituent at any substitutable positiontherein, for which the same or different, one or two or more, preferably1 or 2 substituents may be selected from the group consisting of ahalogen atom, a lower alkyl group, a halo-lower alkyl group, ahydroxy-lower alkyl group and a lower alkoxy group.

The halogen atom for the substituent is, for example, preferably afluorine atom, a chlorine atom.

The lower alkyl group for the substituent is, for example, preferably amethyl group, an ethyl group.

The halo-lower alkyl group for the substituent is, for example,preferably a fluoromethyl group, a difluoromethyl group, atrifluoromethyl group.

The hydroxy-lower alkyl group for the substituent is, for example,preferably a hydroxymethyl group, a 2-hydroxyethyl group.

The lower alkoxy group for the substituent is, for example, preferably amethoxy group, an ethoxy group.

The substituent is, for example, preferably a halogen atom, a loweralkyl group, a lower alkoxy group.

The “aryl group” itself of the aryl group optionally having theabove-mentioned substituent for Ar^(a) is, for example, preferably aphenyl group. The “heteroaromatic group” itself of the heteroaromaticgroup optionally having the above-mentioned substituent for Ar^(a) is,for example, preferably a pyridyl group.

Accordingly, preferred examples of the aryl group or the heteroaromaticgroup optionally having the above-mentioned substituent for Ar^(a)includes, for example, a phenyl group, a 4-methoxyphenyl group, a2-pyridyl group, a 6-methyl-2-pyridyl group.

The lower alkylene group for Q⁵ is, for example, preferably a methylenegroup, an ethylene group.

One or two or more methylene groups constituting the lower alkylenegroup for Q⁵ may be independently replaced by an oxygen atom, a sulfuratom or a carbonyl group, and/or substituted by a halogen atom or alower alkyl group. Examples of the replaced or substituted groups arepreferably selected from the following formula (bb4):

Accordingly, concretely, the group of -Q⁵-Ar^(a) is, for example,preferably a benzyl group, a benzoyl group, a phenoxy group, a benzyloxygroup, a 4-methoxybenzyloxy group, a 2-pyridyl group.

The substituent for “an aryl group, an aralkyl group or a heteroaromaticgroup” of R² is, for example, preferably a group of-Q⁴-A⁴(R^(1g))R^(1h).

The “aryl group” itself of the aryl group optionally having theabove-mentioned substituent for R² is, for example, preferably a phenylgroup.

The “aralkyl group” itself of the aralkyl group optionally having theabove-mentioned substituent for R² is, for example, preferably a benzylgroup.

The “heteroaromatic group” itself of the heteroaromatic group optionallyhaving the above-mentioned substituent for R² is, for example,preferably a thienyl group, a pyrazolyl group, a pyridyl group.

Concretely, therefore, the aryl group, the aralkyl group or theheteroaromatic group optionally having the above-mentioned substituentfor R² is, for example, preferably a phenyl group, a 3-cyanophenylgroup, a 3-nitrophenyl group, a 3-carboxyphenyl group, a 3-aminophenylgroup, a 3-dimethylaminomethylphenyl group, a3-methylsulfonylaminophenyl group, a 3-carbamoylphenyl group, a3-methylcarbamoylphenyl group, a 3-dimethylcarbamoylphenyl group, a3-hydroxymethylphenyl group, a 4-hydroxymethylphenyl group, a3-(1-hydroxy-1-methylethyl)phenyl group, a 3-methoxycarbonylphenylgroup, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 3-thienylgroup, a 1-methyl-3-pyrazolyl group, a 2-pyridyl group, a 3-pyridylgroup, a 4-pyridyl group, a 5-fluoro-2-pyridyl group, a6-fluoro-2-pyridyl group, a 6-bromo-2-pyridyl group, a 5-cyano-2-pyridylgroup, a 5-carboxy-2-pyridyl group, a 4-methylaminomethyl-2-pyridylgroup, a 6-amino-2-pyridyl group, a 6-dimethylaminomethyl-2-pyridylgroup, a 6-isopropylmethylamino-2-pyridyl group, a6-(1-amino-1-methylethyl)-2-pyridyl group, a6-(N-methyl-N-acetylaminomethyl)-2-pyridyl group, a6-(N-methyl-N-methoxycarbonylaminomethyl)-2-pyridyl group, a6-(N-methyl-N-methylsulfonylaminomethyl)-2-pyridyl group, a6-dimethylcarbamoyl-2-pyridyl group, a 6-acetyl-2-pyridyl group, a4-methyl-2-pyridyl group, a 6-methyl-2-pyridyl group, a6-(1-fluoro-1-methylethyl)-2-pyridyl group, a5-trifluoromethyl-2-pyridyl group, a 6-hydroxymethyl-2-pyridyl group, a6-(1-hydroxyethyl)-2-pyridyl group, a6-(1-hydroxy-1-methylethyl)-2-pyridyl group, a6-(2-hydroxy-1,1-dimethylethyl)-2-pyridyl group, a6-(2-hydroxy-2-methylpropyl)-2-pyridyl group, a6-(2-hydroxy-1,1-dimethylpropyl)-2-pyridyl group, a6-(1-methoxycarbonyl-1-methylethyl)-2-pyridyl group, a6-methoxy-2-pyridyl group, a 6-(2-hydroxyethoxy)-2-pyridyl group, a5-methoxycarbonyl-2-pyridyl group, a 6-(tert-butoxycarbonyl)-2-pyridylgroup, a 6-(1-hydroxycyclobutyl)-2-pyridyl group, a6-(4-hydroxy-tetrahydropyran-4-yl)-2-pyridyl group, a6-(2-oxo-1-pyrrolidinyl)-2-pyridyl group, or a6-(3-methyl-2-oxoimidazolidin-1-yl)-2-pyridyl group; more preferably aphenyl group, a 3-dimethylaminomethylphenyl group, a3-dimethylcarbamoylphenyl group, a 3-(1-hydroxy-1-methylethyl)phenylgroup, a 3-thienyl group, a 2-pyridyl group, a 5-fluoro-2-pyridyl group,a 6-amino-2-pyridyl group, a6-(N-methyl-N-methylsulfonylaminomethyl)-2-pyridyl group, a6-methyl-2-pyridyl group, a 6-(1-hydroxy-1-methylethyl)-2-pyridyl group,a 6-(2-hydroxy-1,1-dimethylethyl)-2-pyridyl group, a6-(2-hydroxy-2-methylpropyl)-2-pyridyl group, a6-(2-hydroxy-1,1-dimethylpropyl)-2-pyridyl group, a6-(2-hydroxyethoxy)-2-pyridyl group, a 6-(1-hydroxycyclobutyl)-2-pyridylgroup, a 6-(2-oxo-1-pyrrolidinyl)-2-pyridyl group, or a6-(3-methyl-2-oxoimidazolidin-1-yl)-2-pyridyl group, even morepreferably a 6-(1-hydroxy-1-methylethyl)-2-pyridyl group etc.

R² is preferably a lower alkyl group, or an aryl or heteroaromatic groupoptionally having the above-mentioned substituent.

Preferred embodiments of R¹ and R² in formula (I) are, for example, R¹is a lower alkenyl or lower alkynyl, more preferably lower alkenyl groupoptionally substituted by a halogen atom, and R² is a phenyl or pyridyl,more preferably pyridyl group having a group of -Q⁴-A⁴(R^(1g))R^(1h).

R³ is a hydrogen atom or a lower alkyl group, for example, preferably ahydrogen atom, a methyl group or an ethyl group; more preferably ahydrogen atom.

R⁴ is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkylgroup or a group of —N(R^(1k))R^(1m).

The halogen atom for R⁴ is, for example, preferably a fluorine atom, achlorine atom.

The lower alkyl group for R⁴ is, for example, preferably a methyl group,an ethyl group, an isopropyl group.

In the group of —N(R^(1k))R^(1m) for R⁴, R^(1k) and R^(1m) areindependently a hydrogen atom or a lower alkyl group.

The lower alkyl group for R^(1k) and R^(1m) is, for example, preferablya methyl group, an ethyl group, an isopropyl group.

Accordingly, the group of —N(R^(1k))R^(1m) includes, for example, anamino group, a methylamino group, a dimethylamino group, anisopropylmethylamino group.

R⁴ is preferably a hydrogen atom.

T and U are independently a nitrogen atom or a methine group, andpreferably they are both nitrogen atoms.

In the compounds of the formula (I), compounds wherein R¹ is a methylgroup and R² is an unsubstituted phenyl group are excluded from theinvention.

Compounds of a general formula (I-1):

wherein R⁵ and R⁶ are independently a hydrogen atom, a halogen atom, alower alkyl group, a halo-lower alkyl group, a hydroxy-lower alkylgroup, a lower alkoxy group, a lower alkanoyl group, a hydroxy-loweralkylamino group, a carbamoyl group or a hydroxy-lower alkylcarbamoylgroup; R¹⁰ is a lower alkyl group, a lower alkenyl group or a loweralkynyl group, which may be substituted by a halogen atom; R²⁰ is anaryl group or a heteroaromatic group, which may have a substituentselected from a group consisting of a halogen atom, a cyano group, anitro group, a carboxyl group, a group of -Q⁴-A⁴(R^(1g))R^(1h) and agroup of -Q⁵-Ar^(a); and A¹, A², A⁴, Ar^(a), Q¹, Q², Q⁴, Q⁵, R^(1a),R^(1b), R^(1g) and R^(1h) have the same meanings as above, provided thatthe compounds wherein R¹⁰ is a methyl group and R²⁰ is an unsubstitutedphenyl group are excluded;compounds of a general formula (I-2):

wherein R¹¹ is a group of a formula (a-1) or (a-2):

R^(7a), R^(7b), R^(8a) and R^(8b) are independently a hydrogen atom, ahalogen atom or a cyano group; R^(8c) is a hydrogen atom or a loweralkyl group; A¹, A², Q¹, Q², R^(1a), R^(1b), R⁵, R⁶ and R²⁰ have thesame meanings as above;and compounds of a general formula (I-3):

wherein R¹² is a group of a formula (a-1):

R^(7a) and R^(7b) are independently a hydrogen atom, a halogen atom or acyano group; R²¹ is a lower alkyl group; A¹, A², Q¹, Q², R^(1a), R^(1b),R⁵ and R⁶ have the same meanings as above are within the scope of thecompounds of formula (I).

Preferred examples and preferred embodiments of R⁵ and R⁶ in thecompounds of formulae (I-1), (I-2) and (I-3) are described below.

The halogen atom for R⁵ and R⁶ is, for example, preferably a fluorineatom, a chlorine atom.

The alkyl group for R⁵ and R⁶ is, for example, preferably a methylgroup, an ethyl group.

The halo-lower alkyl group for R⁵ and R⁶ is, for example, preferably afluoromethyl group, a difluoromethyl group, a trifluoromethyl group.

The hydroxy-lower alkyl group for R⁵ and R⁶ is, for example, preferablya hydroxymethyl group, a 2-hydroxyethyl group.

The lower alkoxy group for R⁵ and R⁶ is, for example, preferably amethoxy group, an ethoxy group.

The lower alkanoyl group for R⁵ and R⁶ is, for example, preferably anacetyl group.

The hydroxy-lower alkylamino group for R⁵ and R⁶ is, for example,preferably a hydroxymethylamino group, a 2-hydroxyethylamino group.

The hydroxy-lower alkylcarbamoyl group for R⁵ and R⁶ is, for example,preferably a hydroxymethylcarbamoyl group, a 2-hydroxyethylcarbamoylgroup.

Preferred embodiments of R⁵ and R⁶ are, for example, such that both ofthem are hydrogen atoms, or any one of them is a hydrogen atom and theother is a lower alkyl group, a hydroxy-lower alkyl group, a loweralkoxy group or a lower alkanoyl group.

Preferred embodiments of the group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b) in thecompounds of formulae (I-1), (I-2) and (I-3) may be the same as those ofthe group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b) in formula (I).

Preferred examples and preferred embodiments of R¹⁰ and R²⁰ in formula(I-1) are described below.

The lower alkyl group optionally substituted by a halogen atom for R¹⁰is, for example, preferably a methyl group, an ethyl group, a propylgroup, an isopropyl group, a 2,2-difluoroethyl group, a2,2,2-trifluoroethyl group, more preferably an ethyl group, or anisopropyl group.

The lower alkenyl group optionally, substituted by a halogen atom forR¹⁰ is, for example, preferably an allyl group, a 2-methyl-2-propenylgroup, a 3-methyl-2-butenyl group; more preferably an allyl group.

The lower alkynyl group optionally substituted by a halogen atom for R¹⁰is, for example, preferably a 2-propynyl group.

Preferred embodiments of R¹⁰ are, for example, a lower alkyl groupoptionally substituted by a halogen atom, more concretely, an ethylgroup and an isopropyl group etc.

Another preferred embodiments of R¹⁰ are, for example, a lower alkenylgroup optionally substituted by a halogen atom, more concretely, anallyl group, a 2-methyl-2-propenyl group, a 3-methyl-2-butenyl group;more preferably an allyl group.

Another preferred embodiments of R¹⁰ are, for example, a lower alkynylgroup optionally substituted by a halogen atom, more concretely, a2-propynyl group.

Especially a lower alkenyl group such as an allyl group etc. ispreferred for R¹⁰.

Preferred embodiments of “an aryl group or a heteroaromatic group, whichmay have a substituent selected from a group consisting of a halogenatom, a cyano group, a nitro group, a carboxyl group, a group of-Q⁴-A⁴(R^(1g))R^(1h) and a group of -QS-Ar^(a)” for R²⁰ may be the sameas those of “an aryl group or a heteroaromatic group, which may have asubstituent selected from a group consisting of a halogen atom, a cyanogroup, a nitro group, a carboxyl group, a group of -Q⁴-A⁴(R^(19g))R^(1b)and a group of -Q⁵-Ar^(a)” for R² in formula (I).

Preferred embodiments of R²⁰ are, for example, a phenyl or pyridyl, morepreferably pyridyl group having a group of -Q⁴-A⁴(R^(1g))R^(1h).

Preferred embodiments of R¹⁰ and R²⁰ in formula (I-1) are, for example,R¹⁰ is a lower alkenyl or lower alkynyl, more preferably lower alkenylgroup optionally substituted by a halogen atom, and R²⁰ is a phenyl orpyridyl, more preferably pyridyl group having a group of-Q⁴-A⁴(R^(1g))R^(1h).

Preferred embodiments of R¹⁰, R²⁰ and the group of-Q¹-A¹-Q²-A²(R^(1a))R^(1b) in formula (I-1) are, for example, R¹⁰ is alower alkenyl or lower alkynyl, more preferably lower alkenyl groupoptionally substituted by a halogen atom, R²⁰ is a phenyl or pyridyl,more preferably pyridyl group having a group of -Q⁴-A⁴(R^(1g))R^(1h),and the group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b) is selected from the formula(aa1′):

In the compounds of the formula (I-1), compounds wherein R¹⁰ is a methylgroup and R²⁰ is an unsubstituted phenyl group are excluded from theinvention.

Preferred examples and preferred embodiments of R¹¹ and R²⁰ in formula(I-2) are described below.

The halogen atom for R^(7a), R^(7b), R^(8a) and R^(8b) in the group offormula (a-1) or (a-2) for R¹¹ is, for example, preferably a fluorineatom, a chlorine atom; and the lower alkyl group for R^(8c) is, forexample, preferably a methyl group, an ethyl group.

Preferred embodiments of R^(7a) and R^(7b) are such that they are bothhydrogen atoms, or one of them is a hydrogen atom and the other is ahalogen atom or a cyano group.

Preferred examples of the group of formula (a-1) are, for example, a2-chlorophenyl group, a 2,6-dichlorophenyl group, a2-chloro-6-cyanophenyl group.

A preferred embodiment of R^(8a) and R^(8b) is, for example, such thatthey are both hydrogen atoms.

Accordingly, preferred examples of the group of formula (a-2) are, forexample, a benzyl group, an α-methylbenzyl group.

Preferred examples and preferred embodiments of R¹² and R²¹ in formula(I-3) are described below.

Preferred embodiments of the group of formula (a-1) for R¹² may be thesame as those of formula (a-1) in formula (I-2).

The lower alkyl group for R²¹ is, for example, preferably a methylgroup, an ethyl group.

The terms “any substitutable position” mean positions havingsubstitutable hydrogen(s) on carbon, nitrogen, oxygen and/or sulfuratom(s) where the substitution of hydrogen is chemically allowed and thesubstitution results in a stable compound.

In the compounds of the invention, the replacement for methylenegroup(s) constituting the lower alkylene group by various radicals suchas oxygen, sulfur, sulfinyl, sulfonyl, carbonyl, vinylene, andsubstituted or unsubstituted imine is allowed in case that thereplacement is chemically allowed and the replacement results in astable compound.

Depending on the type of the substituent and the salt form thereof, thecompounds of the invention may be in the form of stereoisomers andtautomers such as optical isomers, diastereomers, geometrical isomers;and the compounds of the invention include all those stereoisomers andtautomers and their mixtures.

The invention includes various crystals, amorphous forms, salts,hydrates and solvates of the compounds of the invention.

Further, prodrugs of the compounds of the invention are within the scopeof the invention. In general, such prodrugs are functional derivativesof the compounds of the invention that can be readily converted intocompounds that are needed by living bodies. Accordingly, in the methodof treatment of various diseases in the invention, the term“administration” includes not only the administration of a specificcompound but also the administration of a compound which, afteradministered to patients, can be converted into the specific compound inthe living bodies. Conventional methods for selection and production ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985, which is referred to hereinand is entirely incorporated herein as a part of the presentdescription. Metabolites of these compounds include active compoundsthat are produced by putting the compounds of the invention in abiological environment, and are within the scope of the invention.

Examples of the compounds of formula (I) and their salts and esters are,for example, the compounds and their salts and esters described inExamples; and more preferred are the following compounds:

-   3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide,-   2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   2-allyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   3-(2-ethyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide,-   2-allyl-6-{[3-hydroxymethyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   2-allyl-1-(6-aminopyridin-2-yl)-6-[{4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   2-allyl-6-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   6-{[4-(4-acetylpiperazin-1-yl)phenyl]amino}-2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   2-allyl-6-({4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}amino)-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1-[6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   N-{[6-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-2-yl]methyl}-N-methylmethanesulfonamide,-   2-benzyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-phenyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   2-(2-chlorophenyl)-1-[6-(1-hydroxycyclobutyl)pyridin-2-yl]-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-2-isopropyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-2-isopropyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-2-isopropyl-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,    and-   2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,    more preferably,-   3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide,-   2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,-   1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-2-isopropyl-6-[4-(1-methylpiperidin-4-yl)phenyl]amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,    and-   2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.

Methods for producing the compounds of the invention are describedbelow. Compounds (I) of the invention may be produced, for example,according to the production methods mentioned below or according to themethods shown in Examples and Production Examples. However, theproduction methods for compounds (I) of the invention should not belimited to those reaction examples.

Production Method 1

A compound of a general formula (II):

wherein;

L¹ is a leaving group;

R^(1p) is a lower alkyl group, a lower alkenyl group, a lower alkynylgroup or a cyclo-lower alkyl group, which may be substituted by ahalogen atom, or is an aryl group, an aralkyl group or a heteroaromaticgroup, which may have a substituent selected from a group consisting ofa halogen atom, a cyano group, a lower alkyl group and anoptionally-protected amino group;

R^(2p) is a hydrogen atom, a lower alkyl group, a lower alkenyl group ora lower alkynyl group, or is an aryl group, an aralkyl group or aheteroaromatic group, which may have a substituent selected from a groupconsisting of a halogen atom, a cyano group, a nitro group, a group of-Q^(4p)-A^(4p)(R^(1gp))R^(1hp), a group of -Q^(5p)-Ar^(ap) and anoptionally-protected carboxyl group, wherein one or two or moremethylene groups constituting the lower alkyl group, the lower alkenylgroup or the lower alkynyl group may be independently replaced by anoxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, anoptionally-protected carbonyl group or a group of —N(R^(1jp))—, and/orsubstituted by a halogen atom;

A^(4p) is a nitrogen atom, or is a methine group optionally substitutedby a halogen atom, an optionally-protected hydroxyl group, a lower alkylgroup or an optionally-protected hydroxy-lower alkyl group;

Ar^(ap) is an aryl group or a heteroaromatic group, which may have asubstituent selected from a group consisting of a halogen atom, a loweralkyl group, a halo-lower alkyl group, a lower alkoxy group and anoptionally-protected hydroxy-lower alkyl group;

Q^(4p) is a single bond or a lower alkylene group, wherein one or two ormore methylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom or an optionally-protectedcarbonyl group, and/or substituted by a lower alkyl group;

Q^(5p) is a single bond, an oxygen atom, a sulfur atom, anoptionally-protected carbonyl group or a lower alkylene group, whereinone or two or more methylene groups constituting lower alkylene groupmay be independently replaced by an oxygen atom, a sulfur atom or anoptionally-protected carbonyl group, and/or substituted by a halogenatom or a lower alkyl group;

R^(1gp) and R^(1hp) are independently a hydrogen atom, a halogen atom, acyano group, an optionally-protected hydroxyl group, a lower alkylgroup, a lower alkoxy-lower alkyl group, a lower alkanoyl group, a loweralkoxycarbonyl group or a lower alkylsulfonyl group, or together form alower alkylene group wherein one or two or more methylene groupsconstituting the lower alkylene group may be independently replaced byan oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, anoptionally-protected carbonyl group or a group of —N(R^(1ip))—, and/orsubstituted by a halogen atom or a lower alkyl group;

R^(1ip) is an imino-protective group, a hydrogen atom, a lower alkylgroup or a halo-lower alkyl group;

R^(1bp) is an imino-protective group, a hydrogen atom or a lower alkylgroup;

R^(4p) is a hydrogen atom, a halogen atom, an optionally-protectedhydroxyl group, a lower alkyl group or a group of —N(R^(1kp))R^(1mp);

R^(1kp) and R^(1mp) are independently an amino or imino-protectivegroup, a hydrogen atom or a lower alkyl group; T and U have the samemeanings as above, is reacted with a compound of a general formula (II)or its salt:

wherein;

Ar^(1p) is an aryl group or a heteroaromatic group, which may have asubstituent selected from a group consisting of a halogen atom, a loweralkyl group, a halo-lower alkyl group, a lower alkoxy group, a loweralkanoyl group, a carbamoyl group, a heteroaromatic group optionallysubstituted by a lower alkyl group, a group of-Q^(1p)-A^(1p)-Q²-A^(2p)(R^(1ap))R^(1bp), and an optionally-protectedhydroxy-lower alkyl, hydroxy-lower alkylamino and hydroxy-loweralkylcarbamoyl groups;

A^(1p) is a single bond, an oxygen atom or a sulfur atom, or is an iminogroup optionally substituted by an imino-protective group or a loweralkyl group;

A^(2p) is a nitrogen atom, or is a methine group or a 1-vinyl-2-ylidenegroup which may be substituted by an optionally-protected hydroxylgroup, a lower alkyl group or an optionally-protected hydroxy-loweralkyl group;

Q^(1p) is a single bond, an optionally-protected carbonyl group, or amethylene group optionally substituted by a lower alkyl group;

R^(1ap) and R^(1bp) are independently a hydrogen atom, a lower alkylgroup or an optionally-protected hydroxy-lower alkyl group, or togetherform a lower alkylene group wherein one or two or more methylene groupsconstituting the lower alkylene group may be independently replaced byan oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, anoptionally-protected carbonyl group, a vinylene group or a group of—N(R^(1cp))—, and/or substituted by an optionally-protected hydroxylgroup or a lower alkyl group;

R^(1cp) is a hydrogen atom, a lower alkenyl group, or a group of-Q^(3p)-A^(3p)(R^(1dp))R^(1ep);

A^(3p) is a nitrogen atom, or is a methine group or a 1-vinyl-2-ylidenegroup which may be substituted by an optionally-protected hydroxylgroup, a lower alkyl group or an optionally-protected hydroxy-loweralkyl group;

Q^(3p) is a single bond or a lower alkylene group, wherein one or two ormore methylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom, a sulfur atom, anoptionally-protected carbonyl group, a sulfinyl group or a sulfonylgroup, and/or substituted by a halogen atom, a cyano group, anoptionally-protected hydroxyl group or a lower alkyl group;

R^(1dp) and R^(1ep) are independently a hydrogen atom, a halogen atom, acyano group, an optionally-protected hydroxyl group, a lower alkyl groupor an optionally-protected hydroxy-lower alkyl group, or together form alower alkylene group wherein one or two or more methylene groupsconstituting the lower alkylene group may be independently replaced byan oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, anoptionally-protected carbonyl group, a vinylene group or a group of—N(R^(1fp))—, and/or substituted by an optionally-protected hydroxylgroup or a lower alkyl group;

R^(1fp) is an imino-protective group, a hydrogen atom, a lower alkylgroup, a halo-lower alkyl group, a lower alkenyl group or a loweralkanoyl group; Q² and R³ have the same meanings as above, to give acompound of a general formula (IV):

wherein Ar^(1p), R^(1p), R^(2p), R³, R^(4p), T and U have the samemeanings as above, and optionally the protective group is removed fromit to produce a compound of a general formula (I):

wherein Ar¹, R¹, R², R³, R⁴, T and U have the same meanings as above.

The leaving group for L¹ includes, for example, a halogen atom such as achlorine atom, a bromine atom, an iodine atom; an organic sulfonyl groupsuch as a methylsulfinyl group, a methylsulfonyl group, an ethylsulfonylgroup, a phenylsulfonyl group; and an organic sulfonyloxy group such asa methylsulfonyloxy group, a trifluoromethylsulfonyloxy group, ap-tolylsulfonyloxy group; preferably a chlorine atom, a methylsulfinylgroup, a methylsulfonyl group.

This production method is a general method for producing the compoundsof formula (I).

In the above reaction, when the reactants have an amino group, an iminogroup, a hydroxyl group, a carboxyl group, a carbonyl group or the likethat does not participate in the reaction, then the amino group, theimino group, the hydroxyl group, the carboxyl group and the carbonylgroup may be suitably protected with an amino or imino-protective group,a hydroxyl-protective group, a carboxyl-protective group or acarbonyl-protective group, and thereafter the reactants may be reacted,and after the reaction, the protective group may be removed.

Not specifically defined, “amino or imino-protective group” may be anyone having its function. For example, it includes an aralkyl group suchas a benzyl group, a p-methoxybenzyl group, a 3,4-dimethoxybenzyl group,an o-nitrobenzyl group, a p-nitrobenzyl group, a benzhydryl group, atrityl group; a lower alkanoyl group such as a formyl group, an acetylgroup, a propionyl group, a butyryl group, a pivaloyl group; a benzoylgroup; an arylalkanoyl group such as a phenylacetyl group, aphenoxyacetyl group; a lower alkoxycarbonyl group such as amethoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonylgroup, a tert-butoxycarbonyl group; an aralkyloxycarbonyl group such asa benzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, aphenethyloxycarbonyl group; a lower alkylsilyl group such as atrimethylsilyl group, a tert-butyldimethylsilyl group; atetrahydropyranyl group; a trimethylsilylethoxymethyl group; a loweralkylsulfonyl group such as a methylsulfonyl group, an ethylsulfonylgroup; an arylsulfonyl group such as benzenesulfonyl group, atoluenesulfonyl group; and is especially preferably an acetyl group, abenzoyl group, a tert-butoxycarbonyl group, a trimethylsilylethoxymethylgroup, a methylsulfonyl group.

Not specifically defined, “hydroxyl-protective group” may be any onehaving its function. For example, it includes a lower alkyl group suchas a methyl group, an ethyl group, a propyl group, an isopropyl group, atert-butyl group; a lower alkylsilyl group such as a trimethylsilylgroup, a tert-butyldimethylsilyl group; a lower alkoxymethyl group suchas a methoxymethyl group, a 2-methoxyethoxymethyl group; atetrahydropyranyl group; a trimethylsilylethoxymethyl group; an aralkylgroup such as a benzyl group, a p-methoxybenzyl group, a2,3-dimethoxybenzyl group, an o-nitrobenzyl group, a p-nitrobenzylgroup, a trityl group; an acyl group such as a formyl group, an acetylgroup; and is especially preferably a methyl group, a methoxymethylgroup, a tetrahydropyranyl group, a trityl group, atrimethylsilylethoxymethyl group, a tert-butyldimethylsilyl group, anacetyl group.

Not specifically defined, “carboxyl-protective group” may be any onehaving its function. For example, it includes a lower alkyl group suchas a methyl group, an ethyl group, a propyl group, an isopropyl group, atert-butyl group; a halo-lower alkyl group such as a2,2,2-trichloroethyl group; a lower alkenyl group such as an allylgroup; an aralkyl group such as a benzyl group, a p-methoxybenzyl group,a p-nitrobenzyl group, a benzhydryl group, a trityl group; and isespecially preferably a methyl group, an ethyl group, a tert-butylgroup, an allyl group, a benzyl group, a p-methoxybenzyl group, abenzhydryl group.

Not specifically defined, “carbonyl-protective group” may be any onehaving its function. For example, it includes acetals and ketals such asethylene ketal, trimethylene ketal, dimethylene ketal.

For the reaction of the compound of formula (II) and the compound offormula (III), in general, an equimolar or excessive molar amount,preferably from an equimolar amount to 1.5 mols of the compound (III) isused relative to one mol of the compound (II).

The reaction is attained generally in an inert solvent. The inertsolvent is, for example, preferably toluene, benzene, methylenechloride, chloroform, tetrahydrofuran, dioxane, dimethylformamide,N-methylpyrrolidone, dimethylsulfoxide and their mixed solvents.

Preferably, the reaction is attained in the presence of a base. The baseincludes, for example, organic bases such as triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine; and inorganicbases such as sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide.

The amount of the base to be used may be generally from an equimolaramount to an excessive molar amount, preferably from 1 to 3 molsrelative to one mol of the compound of formula (II).

The reaction temperature may be generally from 0° C. to 200° C.,preferably from 20° C. to 150° C.

The reaction time may be generally from 5 minutes to 7 days, preferablyfrom 30 minutes to 24 hours.

After the reaction, the system may be processed in an ordinary manner toobtain a crude product of the compound of formula (IV). Thus obtained,the compound of formula (IV) is purified in an ordinary manner, or notpurified, optionally it is processed for removing the protective groupof the amino group, the hydroxyl group, the carboxyl group and thecarbonyl group therein, optionally as suitably combined, therebyproducing the compound of formula (I).

The method of removing the protective group varies, depending on thetype of the protective group and on the stability of the intendedcompound (I). For example, the deprotection may be attained according tomethods described in references [see Protective Groups in OrganicSynthesis, 3rd. Ed., by T. W. Greene, John Wiley & Sons (1999)] oraccording to methods similar thereto. For example, herein employable area method of solvolysis with an acid or a base, which comprisesprocessing the protected compound with from 0.01 mols to a largeexcessive amount of an acid, preferably trifluoroacetic acid, formicacid or hydrochloric acid, or with from an equimolar amount to a largeexcessive amount of a base, preferably potassium hydroxide or calciumhydroxide; and a method of chemical reduction with a metal hydridecomplex, or catalytic reduction with a palladium-carbon catalyst or aRaney nickel catalyst.

The compounds of formula (I) may be readily isolated and purified in anyordinary separation method. Examples of the method are, for example,solvent extraction, recrystallization, column chromatography,preparative thin-layer chromatography.

The compounds may be converted into their pharmaceutically-acceptablesalts or esters in an ordinary manner; and on the contrary, their saltsor esters may also be converted into free compounds in an ordinarymanner.

“Salts” of the compound of formula (III) mean ordinary salts used in thefield of organic chemistry. For example, when the compound has acarboxyl group, then its salts are base-addition salts at the carboxylgroup; and when the compound has an amino group or a basic heterocyclicgroup, then its salt are acid-addition salts at the amino group or thebasic heterocyclic group.

The base-addition salts include, for example, alkali metal salts such assodium salts, potassium salts; alkaline earth metal salts such ascalcium salts, magnesium salts; ammonium salts; organic amine salts suchas trimethylamine salts, triethylamine salts, dicyclohexylamine salts,ethanolamine salts, diethanolamine salts, triethanolamine salts,procaine salts, N,N′-dibenzylethylenediamine salts.

The acid-addition salts include, for example, inorganic acid salts suchas hydrochlorides, sulfates, nitrates, phosphates, perchlorates; organicacid salts such as maleates, fumarates, tartrates, citrates, ascorbates,trifluoroacetates; sulfonates such as methanesulfonates, isethionates,benzenesulfonates, p-toluenesulfonates.

The compounds of formulae (II) and (III) may be commercially available,or may be produced according to methods described in references [seeWO2006/004040, WO2003/037872; Journal of Medicinal Chemistry, Vol. 48,pp. 2371-2387; Bioorg. & Med. Chem. Lett., Vol. 14, pp. 5793-5797;Journal of the Chemical Society, Perkin Transaction II, Vol: 3, p. 843]or according to methods similar thereto, or according to the methodsdescribed below, or according to the methods described in Examples andProduction Examples, optionally as suitably combined.

Production Method A

wherein Et is an ethyl group; L² is a leaving group; Me is a methylgroup; R^(1p), R^(2p), R^(4p) and U have the same meanings as above.

The production method A is a method for producing a compound of formula(II) where the leaving group for L¹ is a methylsulfinyl group, and T isa nitrogen atom, or that is, a compound of formula (II-1).

According to this production method, the compound of formula (II-1) canbe produced by reacting a compound of formula (1) and a hydrazinederivative of formula (2) in the presence of a base to give a compoundof formula (3), and thereafter introducing a group of OP into thecompound (3) to give a compound (5), and finally oxidizing themethylthio group in the compound (5) into a methylsulfinyl group.

In the step of reacting the compound of formula (1) and the hydrazinederivative of formula (2) in the presence of a base to give the compoundof formula (3), in general, from 0.5 mols to an excessive molar amount,preferably from an equimolar amount to 3.0 mols of the hydrazinederivative (2) is used relative to one mol of the compound (I).

In general, the reaction is attained in an inert solvent. The inertsolvent is, for example, preferably methylene chloride, chloroform,tetrahydrofuran, ethyl ether, benzene, toluene, dimethylformamide, ortheir mixed solvents.

Preferably, the reaction is attained in the presence of a base. The baseincludes, for example, organic bases such as triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine; inorganicbases such as sodium hydroxide, potassium hydroxide, sodium carbonate,potassium carbonate, sodium hydrogencarbonate.

In general; the amount of the base to be used is preferably from anequimolar amount to an excessive molar amount relative to one mol of thecompound (I). When the base is liquid, then the base may serve also as asolvent.

The reaction temperature may be generally from −78° C. to 100° C.,preferably from 20° C. to 80° C.

The reaction time may be generally from 5 minutes to 7 days, preferablyfrom 30 minutes to 24 hours.

In the step of reacting the compound (3) and the compound (4) to givethe compound (5), in general, from 0.5 mols to an excessive molaramount, preferably from 2.0 mols to 5.0 mols of the compound (4) is usedrelative to one mol of the compound (3).

The leaving group for L² is preferably a halogen atom such as a chlorineatom, a bromine atom, an iodine atom.

In general, the reaction may be attained in an inert solvent such astetrahydrofuran, benzene, toluene, acetonitrile, dimethylformamide inthe presence of a base such as sodium hydride, sodium amide, sodiumalkoxide, or in a solvent such as methanol, ethanol, acetonitrile in thepresence of a base such as sodium hydroxide, potassium hydroxide,potassium carbonate.

In general, the reaction temperature is preferably from 0° C. to theboiling point of the solvent used in the reaction; and, in general, thereaction time is preferably from 1 hour to 48 hours.

To the step of oxidizing the methylthio group in the compound (5) toproduce the compound (II-1), applicable is a method of oxidizing amethylthio group into a methylsulfinyl group or a methylsulfonyl groupper se well known in the field of organic chemistry. In general, forexample, in an inert solvent such as benzene, toluene, methylenechloride, chloroform, tetrahydrofuran, acetonitrile ordimethylformamide, from 0.5 mols to an excessive molar amount,preferably from an equimolar amount to 1.5 mols of an oxidizing agentsuch as metachloroperbenzoic acid or oxone may be used relative to onemol of the compound (5) for the oxidization.

The reaction temperature is, in general, preferably from 0° C. to theboiling point of the solvent used in the reaction; and, in general, thereaction time is preferably from 30 minutes to 8 hours.

The compounds of formulae (1) and (2) may be commercially available, ormay be produced according to known methods or according to the methodsdescribed in Examples, or according to methods similar thereto,optionally as suitably combined.

Production Method B

wherein M is an ordinary organic metal atom; R^(100p) is an aryl group,an aralkyl group or a heteroaromatic group, which may have a substituentselected from a group consisting of a halogen atom, a cyano group, alower alkyl group and an optionally-protected amino group; Me, R^(2p),R^(4p) and U have the same meanings as above.

The production method B is a method for producing a compound of formula(II) in which R^(1p) is an aryl group, an aralkyl group or aheteroaromatic group which may have a substituent selected from a groupconsisting of a halogen atom, a cyano group, a lower alkyl group and anoptionally-protected amino group, the leaving group for L¹ is amethylsulfinyl group, and T is a nitrogen atom, or that is, a compoundof formula (II-2).

According to this production method, the compound of formula (II-2) canbe produced by reacting a compound of formula (3), which is producedaccording to the production method A, and an organic metal compound offormula (6) in the presence of a metal salt catalyst or a metal saltreagent to give a compound of formula (7), and then oxidizing themethylthio group in the compound (7) into a methylsulfinyl group.

In the step of producing the compound (7) by reacting the compound (3)and the compound (6), in general, from 0.5 mols to 5 mols, preferablyfrom 0.7 mols to 3 mols of the compound (6) is used relative to one molof the compound (3) in the presence of a metal salt catalyst or a metalsalt reagent.

The metal salt catalyst or the metal salt reagent to be used in thereaction is, for example, a transition metal generally used incross-coupling reaction, such as copper, nickel, palladium; and, forexample, preferred are copper(II) acetate, coppertrifluoromethanesulfonate, copper iodide.

The ordinary organic metal atom for M means an organic metal atomgenerally used in cross-coupling reaction, including, for example,lithium, boron, silicon, magnesium, aluminium, zinc, tin, and morepreferably boron, zinc, tin. Concrete modes in use are, for example,boric acid or borates with boron; zinc chloride, zinc bromide or zinciodide with zinc; and tri-lower alkyl-tin with tin.

The reaction may be attained generally in an inert solvent. The inertsolvent is, for example, preferably water, benzene, toluene, xylene,methylene chloride, chloroform, dimethoxyethane, tetrahydrofuran,dioxane, dimethylformamide, and their mixed solvents.

The reaction temperature may be generally from room temperature to theboiling point of the solvent used in the reaction, preferably from 20°C. to 200° C.

The reaction time is generally from 30 minutes to 7 days, preferablyfrom 24 hours to 3 days.

Preferably, the reaction is attained in the presence of a base. The baseincludes, for example, inorganic bases such as potassium phosphate,sodium hydrogencarbonate, sodium carbonate, potassium carbonate, cesiumcarbonate; and organic bases such as triethylamine, diisopropylamine.

The amount of the base to be used may be generally from 0.5 mols to 5mols, preferably from an equimolar amount to 3 mols relative to one molof the compound (3).

The step of oxidizing the methylthio group in the compound (7) toproduce the compound (II-2) may be attained in the same manner as thatfor the step of oxidizing the methylthio group in the compound (5) toproduce the compound (II-1) in the production method A.

The compound of formula (6) may be commercially available, or may beproduced according to known methods, or according to the methodsdescribed in Examples, or according to methods similar thereto,optionally as suitably combined.

Production Method C

wherein R^(p) is a hydrogen atom, or an imino-protective group; R^(200p)is an aryl group, an aralkyl group or a heteroaromatic group, which mayhave a substituent selected from a group consisting of a halogen atom, acyano group, a nitro group, a group of -Q^(4p)-A^(4p)(R^(1gp))R^(1hp), agroup of -Q^(5p)-Ar^(ap) and an optionally-protected carboxyl group;A^(4p), Ar^(ap), Et, M, Me, Q^(4p), Q^(5p), R^(1gp), R^(1hp), R^(1p),R^(4p) and U have the same meanings as above.

The imino-protective group for R^(p) is, for example, preferably abenzyl group, a paramethoxybenzyl group, a tert-butoxycarbonyl group, abenzyloxycarbonyl group.

The production method C is a method for producing a compound of formula(II) where R^(2p) is an aryl group, an aralkyl group or a heteroaromaticgroup, which may have a substituent selected from a group consisting ofa halogen atom, a cyano group, a nitro group, a group of-Q^(4p)-A^(4p)(R^(1gp))R^(1hp), a group of -Q^(5p)-Ar^(ap) and anoptionally-protected carboxyl group, the leaving group for L¹ is amethylsulfinyl group, and T is a nitrogen atom, or that is, a compoundof formula (II-3).

According to this production method, the compound of formula (II-3) canbe produced by reacting a compound of formula (1) and a hydrazinederivative of formula (8) in the presence of a base, then hydrolyzingthe resulting compound and cyclizing it to give a compound of formula(9), and thereafter reacting the compound (9) with an organic metalcompound of formula (10) in the presence of a catalyst to therebyintroduce a group of R^(200p) thereinto to give a compound (II), andfinally oxidizing the methylthio group in the compound (II) into amethylsulfonyl group.

In the step of reacting the compound of formula (1) and the hydrazinederivative of formula (8) in the presence of a base, in general, theamount of the hydrazine derivative (8) to be used may be from 0.5 molsto an excessive molar amount, preferably from an equimolar amount to 1.5mols relative to one mol of the compound (I).

The reaction may be attained generally in the presence of an organicbase such as triethylamine, diisopropylethylamine, pyridine,4-dimethylaminopyridine, or an inorganic base such as sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate, sodiumhydrogencarbonate, in an inert solvent such as methylene chloride,chloroform, tetrahydrofuran, ethyl ether, benzene, toluene,dimethylformamide, or their mixed solvents.

In general, the amount of the base to be used is preferably from anequimolar amount to an excessive molar amount relative to one mol of thecompound (1). When the base is liquid, the base may serve also as asolvent.

The reaction temperature may be generally from −78° C. to 200° C.,preferably from 20° C. to 100° C.

The reaction time may be generally from 5 minutes to 7 days, preferablyfrom 8 hours to 24 hours.

To the step of hydrolyzing the compound obtained in the above reaction,applicable is a method of hydrolysis of carboxylates per see well knownin the field of organic chemistry. In general, in a solvent such asmethanol, ethanol, tetrahydrofuran, dioxane, water or in their mixedsolvent, the compound may be processed with an acid such as hydrochloricacid or sulfuric acid, or a base such as sodium hydroxide, potassiumhydroxide or calcium hydroxide.

In general, the reaction temperature is preferably from 50° C. to theboiling point of the solvent used in the reaction; and in general, thereaction time is preferably from 1 hour to 48 hours.

After the hydrolysis, the resulting compound is cyclized to produce thecompound (9). For this, the reaction liquid may be made acidic after thehydrolysis, whereupon the cyclization may go on as such. In case wherethe cyclization does not go on, then the hydrolyzed compound may berefluxed under heat in the presence of acetic anhydride, or thehydrolyzed compound may be processed with thionyl chloride to attain theintended cyclization of the compound.

In the cyclization with acetic anhydride, the amount of acetic anhydrideto be used is preferably an excessive molar amount, and the reactiontime is, in general, preferably from 1 hour to 48 hours.

In case where the hydrolyzed compound is processed with thionylchloride, the amount of thionyl chloride to be used is preferably anexcessive molar amount, and the reaction time is, in general, preferablyfrom 1 hour to 48 hours.

The step of reacting the compound (9) with the organic metal compound offormula (10) in the presence of a catalyst to thereby introduce a groupof R^(200p) thereinto to produce the compound (II) may be attained inthe same manner as that for the step of producing the compound (6) fromthe compound (3) in the production method B.

The above step may also be attained, using a halide compound having agroup of R^(200p) in place of the organic metal compound of formula(10). When such a halide compound is used, then the catalyst ispreferably a copper(I) iodide-diamine complex.

The step of oxidizing the methylthio group in the compound (11) toproduce the compound (II-3) may be attained in the same manner as thatfor the step of oxidizing the methylthio group in the compound (5) toproduce the compound (II-1) in the production method A.

The compound of formula (8) may be commercially available, or may beproduced according to known methods or according to the methodsdescribed in Examples, or according to methods similar thereto,optionally as suitably combined.

Production Method D

wherein Et, Me, R^(4p), R^(100p) and U have the same meanings as above.

The production method D is a method for producing a compound of formula(II) in which 1013 is an aryl group, an aralkyl group or aheteroaromatic group, which may have a substituent selected from a groupconsisting of a halogen atom, a cyano group, a lower alkyl group and anoptionally-protected amino group, the leaving group for L¹ is amethylsulfinyl group, and T is a methine group, or that is, a compoundof formula (II-4).

According to this production method, the compound of formula (II-4) canbe produced by reacting a compound of formula (12) and an amino compoundof formula (13), then hydrolyzing the resulting compound and cyclizingit to give a compound of formula (14), and thereafter oxidizing themethylthio group in the compound (14) into a methylsulfinyl group.

In the reaction of the compound of formula (12) and amino compound offormula (13), in general, the amount of the amino compound (13) may befrom 0.5 mols to an excessive molar amount, preferably from an equimolaramount to 1.5 mols relative to one mol of the compound (12).

In general, the reaction may be effected in an inert solvent. The insertsolvent is, for example, preferably methanol, ethanol, methylenechloride, chloroform, tetrahydrofuran, ethyl ether, benzene, toluene,dimethylformamide, or their mixed solvents.

Preferably, the reaction is attained in the presence of a base. The baseincludes, for example, organic bases such as triethylamine,diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine;and inorganic bases such as sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, sodium hydrogencarbonate.

In general, the amount of the base to be used is preferably from anequimolar amount to an excessive molar amount relative to one mol of thecompound (12). When the base is liquid, the base may serve also as asolvent.

In general, the reaction temperature may be from −78° C. to 200° C.,preferably from 20° C. to 120° C.

The reaction time may be generally from 5 minutes to 7 days, preferablyfrom 30 minutes to 24 hours.

To the step of hydrolyzing the compound obtained in the above reaction,applicable is a method of hydrolysis of carboxylates per se well knownin the field of organic chemistry. The step of hydrolysis may beattained in the same manner as that for the step of hydrolysis after thereaction of the compound (I) and the hydrazine compound (8) in theproduction method C.

After the hydrolysis, the resulting compound is cyclized to produce thecompound (14). In this step, for example, the compound obtained afterthe hydrolysis may be processed with a condensing agent such asN,N′-dicyclohexylcarbodiimide, N,N′-diisopropylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide,1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride,benzotriazol-1-yloxy-tris-(dimethylamino)phosphoniumhexafluorophosphate, benzotriazol-1-yloxy-tris-pyrrolidinophosphoniumhexafluorophosphate, bromo-tris(dimethylamino)phosphoniumhexafluorophosphate, diphenylphosphoryl azide, 1,1′-carbonyldiimidazole,in an inert solvent such as methylene chloride, butanol, chloroform,tetrahydrofuran, dimethylformamide, pyridine or their mixture.

In general, the amount of the condensing agent to be used may be from 1mol to an excessive molar amount, preferably from 1 mol to 1.5 molsrelative to one mol of the starting compound.

The reaction temperature may be generally from −50° C. to 100° C.,preferably from −20° C. to 50° C.

The reaction time may be generally from 30 minutes to 7 days, preferablyfrom 1 hour to 24 hours.

The step of oxidizing the methylthio group in the compound (14) toproduce the compound (II-4) may be attained in the same manner as thatfor the step of oxidizing the methylthio group in the compound (5) toproduce the compound (II-1) in the production method A.

The compounds of formulae (12) and (13) may be commercially available,or may be produced according to known methods or according to themethods described in Examples or according to methods similar thereto,optionally as suitably combined.

The pharmaceutical test examples for the compounds of the invention areshown below.

Pharmaceutical Test 1 (Weel Kinase-Inhibitory Effect) (1) Purificationof Weel Kinase:

A cDNA of Weel kinase with glutathione-S-transferase (GST) fused at theamino terminal thereof was inserted into a baculovirus expression vectorto construct a recombinant baculovirus, with which cells of an insectcell line Sf9 were infected for high expression therein. The infectedcells were recovered and solubilized, and then the GST-tagged Weelkinase protein was adsorbed by a glutathione column, and eluted from thecolumn with glutathione, and the active fraction was desalted in adesalting column to give a purified enzyme.

(2) Determination of Weel Kinase Activity:

In determination of the Weel kinase activity, a synthetic peptide,Poly(Lys,Tyr) Hydrobromide (Lys:Tyr (4:1)) bought from Sigma was used asthe substrate.

The amount of the reaction mixture was 21.1 μL; and the composition ofthe reaction buffer was 50 mM Tris-HCl buffer (pH 7.4)/10 mM magnesiumchloride/1 mM dithiothreitol. The purified Weel kinase, 2.5 μg of thesubstrate peptide, 10 μM of non-labeled adenosine triphosphate (ATP) and1 μCi of [γ-³³P]-labeled ATP (2500 Ci/mmol or more) were added to it,and incubated at 30° C. for 30 minutes. Next, 10 μl, of 350 mM phosphatebuffer was added to the reaction mixture to stop the reaction. Thesubstrate peptide was adsorbed by a P81 paper filter 96-well plate, thenwashed a few times with 130 mM phosphate buffer, and its radioactivitywas counted with a liquid scintillation counter. The [γ-³³P]-labeled ATPwas bought from Amersham Bioscience.

To add the test compound to the reaction system, the compound wasdiluted with dimethylsulfoxide (DMSO) to prepare a series of dilutions.1.1 μL of each dilution was added to the reaction system. As a control,1.1 μL, of DMSO was added to the reaction system.

As in Table 1, the compounds of the invention exhibit an excellentWeel-inhibitory activity.

TABLE 1 Compound Weel-Inhibitory Effect (IC50, nM) Example 1 7 Example 37.6 Example 19 13 Example 26 18 Example 29 20 Example 52 12 Example 5311 Example 98 14 Example 99 8.8 Example 111 24 Example 113 6.3 Example137 26 Example 147 24 Example 148 17

The Cdc2 tyrosine 15-phosphorylation-inhibitory effect of the compoundsof formula (1) of the invention is described below.

Pharmaceutical Text 2 (Method of Determining Drug Potency in Cells (Cdc2(Cdk1) Tyrosine 15-Phosphorylation-Inhibitory Effect)) a) Reagents:

Fetal bovine serum (FBS) was obtained from Morgate; media RPMI1640 andDMEM were from Invitrogen; camptothecin was from Sigma; gemcitabine wasfrom Nippon Eli Lilly; nocodazole and protease inhibitor cocktail werefrom Sigma; rabbit anti-Cdc2 antibody and mouse anti-Cdc2 antibody werefrom Santa Cruz Biotechnology; rabbit anti-tyrosine 15-phosphorylatedCdc2 antibody and horseradish peroxidase-labeled anti-mouse IgG antibodywere from Cell Signaling Technology; sure blue reserve TMB peroxidasesubstrate was from Kirkegaard and Perry Laboratories.

b) Cells:

Human non-small cell lung cancer cells (NCI-H1299) and human coloncancer cells (WiDr) were obtained from American Type Culture Collection(ATCC).

c) Method of Effect Determination:

In the method of using NCI-H1299 cells, the cells were suspended inRPMI1640 containing 10% FBS, and the cell suspension was applied to a96-well Nunclondelta-processed plastic plate (bought from Nunc), in anamount of 2000 cells/100 μL/well, in which the cells were incubatedovernight in 5% CO₂-95% air at 37° C. Camptothecin was dissolved indimethylsulfoxide (DMSO), and diluted with RPMI1640 containing 10% FBS,and then this was applied to the plate on which the cells had beenpreviously sowed, in an amount of 50 μL/well in such a manner that thefinal concentration of camptothecin could be 200 nM. Then, the cellswere incubated for 16 hours at 37° C. in 5% CO₂-95% air. The testcompound was stepwise diluted with DMSO, then diluted with 4000 nMnocodazole-containing RPMI1640 containing 10% FBS, and applied to theplate on which the camptothecin-treated cells had been sowed, in anamount of 50 μL/well. The cells were incubated for 8 hours at 37° C. in5% CO₂-95% air, then the medium was removed, and a cytolytic buffer wasadded to the plate in an amount of 100 μL/well, shaken at 4° C. for 2hours, then frozen at −80° C., and melted to give a cell solution. Cdc2and tyrosine 15-phosphorylated Cdc2 in the cell solution were determinedthrough enzyme-linked immunosorbent assay (ELISA), and the ratio oftyrosine 15-phosphorylated Cdc2 to Cdc2 was calculated to obtain the 50%phosphorylation-inhibitory concentration of the test compound to thecells (EC₅₀, nM). The cytolytic buffer used herein is an aqueoussolution containing 20 mM Hepes (pH 7.5), 150 mM sodium chloride, 1 mMdisodium ethylenediaminetetraacetate, 0.1% polyoxyethylene (10)octylphenyl ether, 1% protease inhibitor cocktail, 1 mM dithiothreitol,2 mM sodium orthovanadate, 10 mM sodium fluoride and 10 mM glyceroldiphosphate. Cdc2 was determined through ELISA as follows: A rabbitanti-Cdc2 antibody solution, which had been diluted 200-fold with 50 mMcarbonate-bicarbonate buffer (pH 9.6), was applied to a 96-wellmaxisorpimmuno plate (bought from Nunc), in an amount of 50 μL/well, andstatically kept overnight at 4° C. so as to fix the antibody on theplate. Next, this was washed three times with phosphate-buffered saline(PBS), and 5% bovine serum albumin-containing PBS (5% BSA/PBS) was addedthereto in an amount of 300 μL/well, and statically kept at roomtemperature for 2 hours, and then again washed three times with PBS. Amouse anti-Cdc2 antibody solution that had been diluted 100-fold with0.05% polyoxyethylene sorbitan monolaurate and 1% BSA-containingTris-HCl-buffered saline (1% BSA/TBS-T) was added to it in an amount of50 μL/well, and the cell solution was added thereto in an amount of 5μL/well and statically kept overnight at 4° C. Next, this was washedthree times with 0.05% polyoxyethylene sorbitan monolaurate and 0.1%BSA-containing Tris-HCl-buffered saline (0.1% BSA/TBS-T), and then ahorseradish peroxidase-labeled anti-mouse IgG antibody solution that hadbeen diluted 2000-fold with 1% BSA/TBS-T was added thereto in an amountof 70 μL/well, and statically kept at room temperature for 3 hours.Finally, this was washed five times with 0.1% BSA/TBS-T, then asubstrate of sure blue reserve TMB peroxidase was added to it in anamount of 100 μL/well, and left for coloration in a dark place at roomtemperature for 15 minutes. Then, 1 M hydrochloric acid was added to itin an amount of 100 μL/well to stop the reaction, and this was analyzedthrough colorimetry. Tyrosine 15-phosphorylated Cdc2 was determinedthrough ELISA as follows: A rabbit anti-tyrosine 15-phosphorylated Cdc2antibody solution, which had been diluted 100-fold with 50 mMcarbonate-bicarbonate buffer (pH 9.6), was applied to a 96-wellmaxisorpimmuno plate in an amount of 50 μL/well, and statically keptovernight at 4° C. so as to fix the antibody on the plate. Next, thiswas washed three times with PBS, and 5% BSA/PBS was added thereto in anamount of 300 μL/well, and statically kept at room temperature for 2hours, and then again washed three times with PBS. A mouse anti-Cdc2antibody solution that had been diluted 100-fold with 1% BSA/TBS-T wasadded to it in an amount of 50 pt/well, and the cell solution was addedthereto in an amount of 5 μL/well and statically kept overnight at 4° C.Next, this was washed three times with 0.1% BSA/TBS-T, and then ahorseradish peroxidase-labeled anti-mouse IgG antibody solution that hadbeen diluted 2000-fold with 1% BSA/TBS-T was added thereto in an amountof 70 μL/well, and statically kept at room temperature for 3 hours.Finally, this was washed five times with 0.1% BSA/TBS-T, then asubstrate of sure blue reserve TMB peroxidase was added to it in anamount of 100 μL/well, and left for coloration in a dark place at roomtemperature for 5 minutes. Then, 1 M hydrochloric acid was added to itin an amount of 100 μL/well to stop the reaction, and this was analyzedthrough colorimetry.

In the method of using WiDr cells, the cells were suspended in DMEMcontaining 10% FBS, and the cell suspension was applied to a 96-wellNunclondelta-processed plastic plate in an amount of 2000 cells/100μL/well, in which the cells were incubated overnight in 5% CO₂-95% airat 37° C. Gemcitabine was dissolved in PBS, and diluted with DMEMcontaining 10% FBS, and then this was applied to the plate on which thecells had been previously sowed, in an amount of 50 μL/well in such amanner that the final concentration of gemcitabine could be 100 nM.Then, the cells were incubated for 24 hours at 37° C. in 5% CO₂-95% air.The test compound was stepwise diluted with DMSO, then diluted with 1200nM nocodazole-containing DMEM containing 10% FBS, and applied to theplate on which the gemcitabine-treated cells had been sowed, in anamount of 50 μL/well. The cells were incubated for 8 hours at 37° C. in5% CO₂-95% air, then the culture was removed, and a cytolytic buffer wasadded to the plate in an amount of 100 μL/well, shaken at 4° C. for 2hours, then frozen at −80° C., and melted to give a cell solution. Cdc2and tyrosine 15-phosphorylated Cdc2 in the cell solution were determinedthrough ELISA, and the ratio of tyrosine 15-phosphorylated Cdc2 to Cdc2was calculated to obtain the 50% phosphorylation-inhibitoryconcentration of the test compound to the cells (EC₅₀, nM). Cdc2 wasdetermined through ELISA as follows: A rabbit anti-Cdc2 antibodysolution, which had been diluted 200-fold with 50 mMcarbonate-bicarbonate buffer (pH 9.6), was applied to a 96-well maxisorpplastic plate in an amount of 50 μL/well, and statically kept overnightat 4° C. so as to fix the antibody on the plate. Next, this was washedthree times with PBS, and 5% BSA/PBS was added thereto in an amount of300 μL/well, and statically kept at room temperature for 2 hours, andthen again washed three times with PBS. A mouse anti-Cdc2 antibodysolution that had been diluted 100-fold with 1% BSA/TBS-T was added toit in an amount of 50 μL/well, and the cell solution was added theretoin an amount of 10 μL/well and statically kept overnight at 4° C. Next,this was washed three times with 0.1% BSA/TBS-T, and then a horseradishperoxidase-labeled anti-mouse IgG antibody solution that had beendiluted 2000-fold with 1% BSA/TBS-T was added thereto in an amount of 70μL/well, and statically kept at room temperature for 3 hours. Finally,this was washed five times with 0.1% BSA/TBS-T, then a substrate of sureblue reserve TMB peroxidase was added to it in an amount of 100 μL/well,and left for coloration in a dark place at room temperature for 15minutes. Then, 1 M hydrochloric acid was added to it in an amount of 100μL/well to stop the reaction, and this was analyzed through colorimetry.Tyrosine 15-phosphorylated Cdc2 was determined through ELISA as follows:A rabbit anti-tyrosine 15-phosphorylated Cdc2 antibody solution, whichhad been diluted 100-fold with 50 mM carbonate-bicarbonate buffer (pH9.6), was applied to a 96-well-maxisorp plastic plate in an amount of 50μL/well, and statically kept overnight at 4° C. so as to fix theantibody on the plate. Next, this was washed three times with PBS, and5% BSA/PBS was added thereto in an amount of 300 μL/well, and staticallykept at room temperature for 2 hours, and then again washed three timeswith PBS. A mouse anti-Cdc2 antibody solution that had been diluted100-fold with 1% BSA/TBS-T was added to it in an amount of 50 μL/well,and the cell solution was added thereto in an amount of 10 μL/well andstatically kept overnight at 4° C. Next, this was washed three timeswith 0.1% BSA/TBS-T, and then a horseradish peroxidase-labeledanti-mouse IgG antibody solution that had been diluted 2000-fold with 1%BSA/TBS-T was added thereto in an amount of 70 μL/well, and staticallykept at room temperature for 3 hours. Finally, this was washed fivetimes with 0.1% BSA/TBS-T, then a substrate of sure blue reserve TMBperoxidase was added to it in an amount of 100 μL/well, and left forcoloration in a dark place at room temperature for 10 minutes. Then, 1 Mhydrochloric acid was added to it in an amount of 100 μL/well to stopthe reaction, and this was analyzed through colorimetry.

As in Table 2 and Table 3, the compounds of the invention exhibit anexcellent Cdc2-tyrosine 15 phosphorylation-inhibitory effect humancancer cells (NCI-H1299 and WiDr).

TABLE 2 Cdc2-Y15 Phosphorylation-Inhibitory Effect Compound (H1299, +camptothecin) (EC50, nM) Example 1 104 Example 3 61 Example 19 247Example 26 114 Example 29 188 Example 52 46 Example 53 68 Example 98 83Example 99 86 Example 111 93 Example 137 107 Example 147 100 Example 14879

TABLE 3 Cdc2-Y15 Phosphorylation-Inhibitory Effect Compound (WiDr, +gemcitabine) (EC50, nM) Example 1 143 Example 3 130 Example 19 350Example 53 119 Example 98 39 Example 99 122 Example 113 8 Example 137144 Example 148 86

The checkpoint escape effect of the compounds of formula (1) of theinvention in cells is described below.

Pharmaceutical Text 3 (Method of Determining Drug Potency in Cells(Checkpoint-Removing Effect)) a) Reagents:

Fetal bovine serum (FBS) was obtained from Morgate; DMEM was fromInvitrogen; gemcitabine was from Nippon Eli Lilly; nocodazole and4′,6-diamidino-2-phenylindole were from Sigma; rabbitanti-phosphorylated histone H3 antibody was from Upstate; andfluorescence-labeled (Alexa Fluor 488) anti-rabbit IgG antibody was fromMolecular Probe.

b) Cells:

Human colon cancer cells (WiDr) were obtained from American Type CultureCollection (ATCC).

c) Method of Effect Determination:

The cells were suspended in DMEM containing 10% FBS, and the cellsuspension was applied to a poly-D-lysine-coated 96-well plastic plate(bought from Becton Dickinson) in an amount of 2000 cells/100 μL/well,in which the cells were incubated overnight in 5% CO₂-95% air at 37° C.Gemcitabine was dissolved in phosphate-buffered saline (PBS), anddiluted with DMEM containing 10% FBS, and then this was applied to theplate on which the cells had been previously sowed, in an amount of 50μL/well in such a manner that the final concentration of gemcitabinecould be 100 nM. Then, the cells were incubated for 24 hours at 37° C.in 5% CO₂-95% air. The test compound was stepwise diluted withdimethylsulfoxide, then diluted with 1200 nM nocodazole-containing DMEMcontaining 10% FBS, and applied to the plate on which thegemcitabine-treated cells had been sowed, in an amount of 50 μL/well.The cells were incubated for 8 hours at 37° C. in 5% CO₂-95% air, thenthe culture was removed, and methanol that had been cooled to −20° C.was added to it in an amount of 100 μL/well. Then, the plate was keptovernight at −20° C. so as to fix the cells thereon. Next, themethanol-fixed cells were washed with PBS, and 1% bovine serumalbumin-containing PBS (1% BSA/PBS) was added to it in an amount of 50μL/well, and statically kept at room temperature for 30 minutes, andthen rabbit anti-phosphorylated histone H3 antibody that had beendiluted 250-fold with 1% BSA/PBS was added thereto in an amount of 50μL/well, and statically kept at room temperature for 90 minutes. Next,this was washed with PBS, and a solution containing4′,6-diamidino-2-phenylindole that had been diluted with 1% BSA/PBS tohave a concentration 10 μg/mL and a fluorescence-labeled (Alexa Fluor488) anti-rabbit IgG antibody that had been diluted 250-fold was addedto it in an amount 50 μL/well, and reacted in a dark place at roomtemperature for 60 minutes. Finally, this was washed with PBS, and itsfluorescence intensity was determined to calculate the ratio of thephosphorylated histone H3-positive cells (cells that had been in a celldivision cycle through removal of checkpoint). From this, obtained wasthe 50% checkpoint escape concentration to the cells of the testcompound (EC₅₀, nM).

As in Table 4, the compound of the invention exhibits an excellentcheckpoint escape effect in human cancer cells (WiDr).

TABLE 4 Checkpoint Escape Effect Compound (WiDr + gemcitabine) (EC50,nM) Example 3 268 Example 53 210 Example 147 110 Example 148 100

Pharmaceutical Test 4 (Tumor Growth-Inhibitory Effect)

Human colon cancer cells WiDr (gotten from ATCC) were implanted into thesubcutaneous area of the back of F344/N Jcl-rnu nude rats. Eight daysafter the implantation, gemcitabine (50 mg/kg, Gemzar injection,Eli-Lilly) was intravenously administered to them; and after 24 hours, atest compound was dissolved in a solvent (5% glucose) and given to themthrough continuous intravenous injection for 8 hours. The tumor volume(0.5×(major diameter)×(minor diameter)²) was determined on day 0, 3, 6,10 and 13. Day 0 means the day on which gemcitabine was administered.The relative tumor volume is a relative value, as calculated on thebasis of the tumor volume of 1 on day 0. The tumor growth percentage (%T/C) was obtained according to the following formula:

When the tumor volume change from day 0 in the group subjected to testcompound administration is more than 0 (>0):

% T/C=[(tumor volume change in the test compounds on day 3, 6, 10,13)/(tumor volume change in the control on day 3, 6, 10, 13)]×100.

When the tumor volume change from day 0 in the group subjected to testcompound administration is less than 0 (<0):

% T/C=[(tumor volume change in the test compounds on day 3, 6, 10,13)/(tumor volume change in the test compounds on day 0)]×100.

The data of the tumor growth-inhibiting effect are shown in Table 5.

TABLE 5 % T/C Compound n day 3 day 6 day 10 day 13 Control 4 100 100 100100 Gemcitabine 50 mg/kg 4 22 31 54 65 Compound of Example 53, 3 86 7481 89 0.75 mg/kg/hr Gemcitabine + Compound of 3 −1 3 24 43 Example 53,0.5 mg/kg/hr Gemcitabine + Compound of 4 −20 −37 2 14 Example 53, 0.75mg/kg/hr

Gemcitabine administration reduced the tumor growth percentage, but whengemcitabine is combined with the compound of the invention, then thetumor growth percentage was further reduced. In particular, in the groupwhere the chemical dose was high, the animals showed tumor involution.

As mentioned above, the compound of the invention in combination withother anticancer agent augmented the effect of the other anticanceragent.

Pharmaceutical Test 5 (Method of Determining Drug Potency with Cells(Radiation (X-Ray) Sensitizing Effect))

a) Reagents:

Fetal bovine serum (FBS) was gotten from Morgate; RPMI 1640 medium and0.25% trypsin EDTA were from Invitrogen; cycle test plus DNA reagent kitwas from Becton Dickinson; and nylon net filter was from Millipore.

b) Cells:

Human non-small-cell lung cancer cells (NCI-H1299) were gotten fromATCC.

c) Method of Effect Determination:

NCI-H1299 cells were suspended in 10% FBS-added RPMI 1640 medium, andthe cell suspension was applied to a 6-well Nunclondelta-processedplastic plate bought from Nunc, in an amount of 100,000 cell/2 ml/well,and incubated overnight in 5% CO₂-95% air at 37° C. Using Softex'sM-150WE, the cells were irradiated with 5000 R X-rays, and then furtherincubated in 5% CO₂-95% air at 37° C. for 16 hours. A test compound wasstepwise diluted with DMSO, and applied to a plate with theX-ray-processed cells sowed thereon, in an amount of 2 μL. This wasincubated in 5% CO₂-95% air at 37° C. for 8 hours, and then the culturewas partly taken out. 0.25% trypsin was added to the cells remaining onthe plate, in an amount of 600 pt, and statically kept at roomtemperature to prepare a single cell suspension. The single cellsuspension and the previously-taken culture were mixed for every sample,then centrifuged, and the supernatant was removed. Sampling was thuscompleted. The sample was suspended in a buffer (1 mL) of cycle testplus DNA reagent kid, and frozen and stored at −80° C. The stored samplewas thawed on the test date, centrifuged and the supernatant wasremoved, and this was suspended in cycle test plus A solution (250 μL),left statically at room temperature for 10 minutes, and then B solution(150 μL) was added thereto and further kept statically at roomtemperature for 10 minutes. Next, C solution (150 μL) was added to it,kept statically at 4° C. for 10 minutes, and then filtered through nylonnet filter to thereby complete DNA staining. Using Becton Dickinson'sFACS Calibur, the DNA amount in each cell was quantitatively determinedaccording to a FACS process, and the ratio of the cells having causedDNA fragmentation was determined.

TABLE 6 DNA Fragmentation-Inducing Effect (H1299) (subG1, %) X-rayCompound of Example 53 X-ray + Compound of Example 53 27.1 3.9 54.8

As in Table 6, the compound of the invention has an excellent DNAfragmentation-inducing effect to human-derived cancer cells (NCI-H1299).

As mentioned above, the compound of the invention in combination withX-ray augmented the effect of the X-ray.

The compounds of formula (I) can be administered orally or parenterally,and after formulated into preparations suitable to such administrationmodes, the compounds can be used as pharmaceutical compositions andanticancer agents.

The term “cancer” as referred to in this description includes varioussarcoma and carcinoma and includes solid cancer and hematopoieticcancer. The solid cancer as referred to herein includes, for example,brain tumor, cervicocerebral cancer, esophageal cancer, thyroid cancer,small cell cancer, non-small cell cancer, breast cancer, lung cancer,stomach cancer, gallbladder/bile duct cancer, liver cancer, pancreaticcancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma,uterus body cancer, uterocervical cancer, renal pelvis/ureter cancer,bladder cancer, prostate cancer, penis cancer, testicles cancer, fetalcancer, Wilms' tumor, skin cancer, malignant melanoma, neuroblastoma,osteosarcoma, Ewing's tumor, soft part sarcoma. On the other hand, thehematopoietic cancer includes, for example, acute leukemia, chroniclymphatic leukemia, chronic myelocytic leukemia, polycythemia vera,malignant lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin'slymphoma.

The term “treatment of cancer” as referred to in this description meansthat an anticancer agent is administered to a cancer case so as toinhibit the growth of the cancer cells in the case. Preferably, thetreatment results in cancer growth regression, or that is, it reducesthe size of a detectable cancer. More preferably, the treatment resultsin complete disappearance of cancer.

The compounds of the invention are expected to be effective especiallyto human solid cancer. The human solid cancer includes, for example,brain cancer, cervicocerebral cancer, esophageal cancer, thyroid cancer,small cell cancer, non-small cell cancer, breast cancer, lung cancer,stomach cancer, gallbladder/bile duct cancer, liver cancer, pancreaticcancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma,uterus body cancer, uterocervical cancer, renal pelvis/ureter cancer,bladder cancer, prostate cancer, penis cancer, testicles cancer, fetalcancer, Wilms' cancer, skin cancer, malignant melanoma, neuroblastoma,osteosarcoma, Ewing's tumor, soft part sarcoma, acute leukemia, chroniclymphatic leukemia, chronic myelocytic leukemia, Hodgkin's lymphoma.

The pharmaceutical composition and anticancer agent of the invention maycontain a pharmaceutically acceptable carrier or diluent. Here, the“pharmaceutically acceptable carrier or diluent” refers to excipients[e.g., fats, beeswax, semi-solid and liquid polyols, natural orhydrogenated oils, etc.]; water (e.g., distilled water, particularlydistilled water for injection, etc.), physiological saline, alcohol(e.g., ethanol), glycerol, polyols, aqueous glucose solution, mannitol,plant oils, etc.); additives [e.g., extending agent, disintegratingagent, binder, lubricant, wetting agent, stabilizer, emulsifier,dispersant, preservative, sweetener, colorant, seasoning agent oraromatizer, concentrating agent, diluent, buffer substance, solvent orsolubilizing agent, chemical for achieving storage effect, salt formodifying osmotic pressure, coating agent or antioxidant], and the like.

With regard to each preparation of the pharmaceutical composition andanticancer agent of the invention, various preparation forms can beselected, and examples thereof include oral preparations such astablets, capsules, powders, granules or liquids, or sterilized liquidparenteral preparations such as solutions or suspensions, suppositories,ointments and the like.

Solid preparations can be prepared in the forms of tablet, capsule,granule and powder without any additives, or prepared using appropriatecarriers (additives). Examples of such carriers (additives) may includesaccharides such as lactose or glucose; starch of corn, wheat or rice;fatty acids such as stearic acid; inorganic salts such as magnesiummetasilicate aluminate or anhydrous calcium phosphate; syntheticpolymers such as polyvinylpyrrolidone or polyalkylene glycol; alcoholssuch as stearyl alcohol or benzyl alcohol; synthetic cellulosederivatives such as methylcellulose, carboxymethylcellulose,ethylcellulose or hydroxypropylmethylcellulose; and other conventionallyused additives such as gelatin, talc, plant oil and gum arabic.

These solid preparations such as tablets, capsules, granules and powdersmay generally contain, for example, 0.1 to 100% by weight, andpreferably 5 to 98% by weight, of the compound of the above Formula (I)as an active ingredient, based on the total weight of the preparation.

Liquid preparations are produced in the forms of suspension, syrup,injection and drip infusion (intravenous fluid) using appropriateadditives that are conventionally used in liquid preparations, such aswater, alcohol or a plant-derived oil such as soybean oil, peanut oiland sesame oil.

In particular, when the preparation is administered parenterally in aform of intramuscular injection, intravenous injection or subcutaneousinjection, appropriate solvent or diluent may be exemplified bydistilled water for injection, an aqueous solution of lidocainehydrochloride (for intramuscular injection), physiological saline,aqueous glucose solution, ethanol, polyethylene glycol, propyleneglycol, liquid for intravenous injection (e.g., an aqueous solution ofcitric acid, sodium citrate and the like) or an electrolytic solution(for intravenous drip infusion and intravenous injection), or a mixedsolution thereof.

Such injection may be in a form of a preliminarily dissolved solution,or in a form of powder per se or powder associated with a suitablecarrier (additive) which is dissolved at the time of use. The injectionliquid may contain, for example, 0.1 to 10% by weight of an activeingredient based on the total weight of the preparation.

Liquid preparations such as suspension or syrup for oral administrationmay contain, for example, 0.1 to 10% by weight of an active ingredientbased on the total weight of the preparation.

The preparation can be prepared by a person having ordinary skill in theart according to conventional methods or common techniques. For example,a preparation can be carried out, if the preparation is an oralpreparation, for example, by mixing an appropriate amount of thecompound of the invention with an appropriate amount of lactose andfilling this mixture into hard gelatin capsules which are suitable fororal administration. On the other hand, preparation can be carried out,if the preparation containing the compound of the invention is aninjection, for example, by mixing an appropriate amount of the compoundof the invention with an appropriate amount of 0.9% physiological salineand filling this mixture in vials for injection.

The compounds of the invention may be sued, optionally as combined withany other agent useful for treatment of various cancers or withradiotherapy. The individual ingredients for such combination may beadministered at different times or at the same time as dividedpreparations or one preparation during the term of treatment.Accordingly, the invention should be so interpreted that it includes allmodes of administration at the same time or at different times, and theadministration in this invention should be interpreted so. The scope ofthe combination of the compound of the invention and any other agentuseful for the above-mentioned diseases should include, in principle,any and every combination thereof with any and every pharmaceuticalagent useful for the treatment of the above-mentioned diseases.

Radiation therapy itself means an ordinary method in the field oftreatment of cancer. For radiation therapy, employable are variousradiations such as X-ray, γ-ray, neutron ray, electron beam, protonbeam; and radiation sources. In a most popular radiation therapy, alinear accelerator is used for irradiation with external radiations,γ-ray.

The compounds of the invention may be combined with radiation therapy toenhance the therapeutical effect in radiation therapy; and the compoundsmay be therefore useful as a radiation sensitizer in the field oftreatment of cancer.

Another aspect of the compounds of the invention is that the compoundsare also useful as a sensitizer for any other anticancer agents in thefield of treatment of cancer.

The compounds of the invention may be combined with radiation therapyand/or combined with any other anticancer agents described below intheir use for treatment of cancer.

“Sensitizer” for radiation therapy or anticancer agent as referred toherein is meant to indicate a medical agent which, when used as combinedwith radiation therapy and/or chemotherapy with an anticancer agent, mayadditively or synergistically augment the therapeutical effect of thatradiation therapy and/or chemotherapy.

The agents to be in the combined preparations in the invention may haveany forms selected in any manner, and they may be produced in the samemanner as that for the above-mentioned preparations. The combined agentcomprising the compound of the invention and some other anticancer agentmay be readily produced by anyone skilled in the art according toordinary methods or conventional techniques.

The above-mentioned combination includes not only the compositions ofthe invention that contain one other active substance but also thosecontaining two or more other active substances. There are a lot ofexamples of the combination of the composition of the invention and oneor two or more active substances selected from the remedies for theabove-mentioned diseases.

The agents to be combined with the compositions include, for example, ananticancer agent selected from the group consisting of anticanceralkylating agents, anticancer antimetabolites, anticancer antibiotics,plant-derived anticancer agents, anticancer platinum coordinationcompounds, anticancer camptothecin derivatives, anticancer tyrosinekinase inhibitors, monoclonal antibodies, interferons, biologicalresponse modifiers and other anticancer agents as well aspharmaceutically acceptable salt(s) or ester(s) thereof.

The term “anticancer alkylating agent” as used in the presentspecification refers to an alkylating agent having anticancer activity,and the term “alkylating agent” herein generally refers to an agentgiving an alkyl group in the alkylation reaction in which a hydrogenatom of an organic compound is substituted with an alkyl group. The term“anticancer alkylating agent” may be exemplified by nitrogen mustardN-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan,mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomidecarmustine.

The term “anticancer antimetabolite” as used in the specification refersto an antimetabolite having anticancer activity, and the term“antimetabolite” herein includes, in a broad sense, substances whichdisturb normal metabolism and substances which inhibit the electrontransfer system to prevent the production of energy-rich intermediates,due to their structural or functional similarities to metabolites thatare important for living organisms (such as vitamins, coenzymes, aminoacids and saccharides). The term “anticancer antimetabolites” may beexemplified methotrexate, 6-mercaptopurine riboside, mercaptopurine,5-fluorouracil, tegafur, doxifluridine, carmofur, cytarabine, cytarabineocfosfate, enocitabine, S-1, gemcitabine, fludarabine or pemetrexeddisodium, and preferred are cytarabine, gemcitabine and the like.

The term “anticancer antibiotic” as used in the specification refers toan antibiotic having anticancer activity, and the “antibiotic” hereinincludes substances that are produced by microorganisms and inhibit cellgrowth and other functions of microorganisms and of other livingorganisms. The term “anticancer antibiotic” may be exemplified byactinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin,peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin,zinostatin stimalamer, idarubicin, sirolimus or valrubicin, andpreferred are doxorubicin, mitomycin C and the like.

The term “plant-derived anticancer agent” as used in the specificationincludes compounds having anticancer activities which originate fromplants, or compounds prepared by applying chemical modification to theforegoing compounds. The term “plant-derived anticancer agent” may beexemplified by vincristine, vinblastine, vindesine, etoposide,sobuzoxane, docetaxel, paclitaxel and vinorelbine, and preferred areetoposide and the like.

The term “anticancer camptothecin derivative” as used in thespecification refers to compounds that are structurally related tocamptothecin and inhibit cancer cell growth, including camptothecin perse. The term “anticancer camptothecin derivative” is not particularlylimited to, but may be exemplified by, camptothecin,10-hydroxycamptothecin, topotecan, irinotecan or 9-aminocamptothecin,with camptothecin being preferred. Further, irinotecan is metabolized invivo and exhibits anticancer effect as SN-38. The action mechanism andthe activity of the camptothecin derivatives are believed to bevirtually the same as those of camptothecin (e.g., Nitta, et al., Gan toKagaku Ryoho, 14, 850-857 (1987)).

The term “anticancer platinum coordination compound” as used in thespecification refers to a platinum coordination compound havinganticancer activity, and the term “platinum coordination compound”herein refers to a platinum coordination compound which providesplatinum in ion form. Preferred platinum compounds include cisplatin;cis-diamminediaquoplatinum (II)-ion; chloro(diethylenetriamine)-platinum(II) chloride; dichloro(ethyleriediamine)-platinum (II);diammine(1,1-cyclobutanedicarboxylato) platinum (II) (carboplatin);spiroplatin; iproplatin; diammine(2-ethylmalonato)platinum (II);ethylenediaminemalonatoplatinum (II);aqua(1,2-diaminodicyclohexane)sulfatoplatinum (II);aqua(1,2-diaminodicyclohexane)malonatoplatinum (II);(1,2-diaminocyclohexane)malonatoplatinum (II);(4-carboxyphthalato)(1,2-diaminocyclohexane) platinum (II);(1,2-diaminocyclohexane)-(isocitrato)platinum (II);(1,2-diaminocyclohexane)oxalatoplatinum (II); ormaplatin; tetraplatin;carboplatin, nedaplatin and oxaliplatin, and preferred is cisplatin.Further, other anticancer platinum coordination compounds mentioned inthe specification are known and are commercially available and/orproducible by a person having ordinary skill in the art by conventionaltechniques.

The term “anticancer tyrosine kinase inhibitor” as used in thespecification refers to a tyrosine kinase inhibitor having anticanceractivity, and the term “tyrosine kinase inhibitor” herein refers to achemical substance inhibiting “tyrosine kinase” which transfers aγ-phosphate group of ATP to a hydroxyl group of a specific tyrosine inprotein. The term “anticancer tyrosine kinase inhibitor” may beexemplified by gefitinib, imatinib or erlotinib.

The term “monoclonal antibody” as used in the specification, which isalso known as single clonal antibody, refers to an antibody produced bya monoclonal antibody-producing cell, and examples thereof includecetuximab, bevacizumab, rituximab, alemtuzumab and trastuzumab.

The term “interferon” as used in the specification refers to aninterferon having anticancer activity, and it is a glycoprotein having amolecular weight of about 20,000 which is produced and secreted by mostanimal cells upon viral infection. It has not only the effect ofinhibiting viral growth but also various immune effector mechanismsincluding inhibition of growth of cells (in particular, tumor cells) andenhancement of the natural killer cell activity, thus being designatedas one type of cytokine. Examples of “interferon” include interferon α,interferon α-2a, interferon α-2b, interferon β, interferon γ-1a andinterferon γ-n1.

The term “biological response modifier” as used in the specification isthe so-called biological response modifier or BRM and is generally thegeneric term for substances or drugs for modifying the defensemechanisms of living organisms or biological responses such as survival,growth or differentiation of tissue cells in order to direct them to beuseful for an individual against tumor, infection or other diseases.Examples of the “biological response modifier” include krestin,lentinan, sizofuran, picibanil and ubenimex.

The term “other anticancer agent” as used in the specification refers toan anticancer agent which does not belong to any of the above-describedagents having anticancer activities. Examples of the “other anticanceragent” include mitoxantrone, L-asparaginase, procarbazine, dacarbazine,hydroxycarbamide, pentostatin, tretinoin, alefacept, darbepoetin alfa,anastrozole, exemestane, bicalutamide, leuprorelin, flutamide,fulvestrant, pegaptanib octasodium, denileukin diftitox, aldesleukin,thyrotropin alfa, arsenic trioxide, bortezomib, capecitabine, andgoserelin.

The above-described terms “anticancer alkylating agent”, “anticancerantimetabolite”, “anticancer antibiotic”, “plant-derived anticanceragent”, “anticancer platinum coordination compound”, “anticancercamptothecin derivative”, “anticancer tyrosine kinase inhibitor”,“monoclonal antibody”, “interferon”, “biological response modifier” and“other anticancer agent” are all known and are either commerciallyavailable or producible by a person skilled in the art by methods knownper se or by well-known or conventional methods. The process forpreparation of gefitinib is described, for example, in U.S. Pat. No.5,770,599; the process for preparation of cetuximab is described, forexample, in WO 96/40210; the process for preparation of bevacizumab isdescribed, for example, in WO 94/10202; the process for preparation ofoxaliplatin is described, for example, in U.S. Pat. Nos. 5,420,319 and5,959,133; the process for preparation of gemcitabine is described, forexample, in U.S. Pat. Nos. 5,434,254 and 5,223,608; and the process forpreparation of camptothecin is described in U.S. Pat. Nos. 5,162,532,5,247,089, 5,191,082, 5,200,524, 5,243,050 and 5,321,140; the processfor preparation of irinotecan is described, for example, in U.S. Pat.No. 4,604,463; the process for preparation of topotecan is described,for example, in U.S. Pat. No. 5,734,056; the process for preparation oftemozolomide is described, for example, in JP-B No. 4-5029; and theprocess for preparation of rituximab is described, for example, in JP-WNo. 2-503143.

The above-mentioned anticancer alkylating agents are commerciallyavailable, as exemplified by the following: nitrogen mustard N-oxidefrom Mitsubishi Pharma Corp. as Nitromin (tradename); cyclophosphamidefrom Shionogi & Co., Ltd. as Endoxan (tradename); ifosfamide fromShionogi & Co., Ltd. as Ifomide (tradename); melphalan fromGlaxoSmithKline Corp. as Alkeran (tradename); busulfan from TakedaPharmaceutical Co., Ltd. as Mablin (tradename); mitobronitol from KyorinPharmaceutical Co., Ltd. as Myebrol (tradename); carboquone from SankyoCo., Ltd. as Esquinon (tradename); thiotepa from Sumitomo PharmaceuticalCo., Ltd. as Tespamin (tradename); ranimustine from Mitsubishi PharmaCorp. as Cymerin (tradename); nimustine from Sankyo Co., Ltd. as Nidran(tradename); temozolomide from Schering Corp. as Temodar (tradename);and carmustine from Guilford Pharmaceuticals Inc. as Gliadel Wafer(tradename).

The above-mentioned anticancer antimetabolites are commerciallyavailable, as exemplified by the following: methotrexate from TakedaPharmaceutical Co., Ltd. as Methotrexate (tradename); 6-mercaptopurineriboside from Aventis Corp. as Thioinosine (tradename); mercaptopurinefrom Takeda Pharmaceutical Co., Ltd. as Leukerin (tradename);5-fluorouracil from Kyowa Hakko Kogyo Co., Ltd. as 5-FU (tradename);tegafur from Taiho Pharmaceutical Co., Ltd. as Futraful (tradename);doxyfluridine from Nippon Roche Co., Ltd. as Furutulon (tradename);carmofur from Yamanouchi Pharmaceutical Co., Ltd. as Yamafur(tradename); cytarabine from Nippon Shinyaku Co., Ltd. as Cylocide(tradename); cytarabine ocfosfate from Nippon Kayaku Co., Ltd. asStrasid (tradename); enocitabine from Asahi Kasei Corp. as Sanrabin(tradename); S-1 from Taiho Pharmaceutical Co., Ltd. as TS-1(tradename); gemcitabine from Eli Lilly & Co. as Gemzar (tradename);fludarabine from Nippon Schering Co., Ltd. as Fludara (tradename); andpemetrexed disodium from Eli Lilly & Co. as Alimta (tradename).

The above-mentioned anticancer antibiotics are commercially available,as exemplified by the following: actinomycin D from Banyu PharmaceuticalCo., Ltd. as Cosmegen (tradename); doxorubicin from Kyowa Hakko KogyoCo., Ltd. as adriacin (tradename); daunorubicin from Meiji Seika KaishaLtd. as Daunomycin; neocarzinostatin from Yamanouchi Pharmaceutical Co.,Ltd. as Neocarzinostatin (tradename); bleomycin from Nippon Kayaku Co.,Ltd. as Bleo (tradename); pepromycin from Nippon Kayaku Co, Ltd. asPepro (tradename); mitomycin C from Kyowa Hakko Kogyo Co., Ltd. asMitomycin (tradename); aclarubicin from Yamanouchi Pharmaceutical Co.,Ltd. as Aclacinon (tradename); pirarubicin from Nippon Kayaku Co., Ltd.as Pinorubicin (tradename); epirubicin from Pharmacia Corp. asPharmorubicin (tradename); zinostatin stimalamer from YamanouchiPharmaceutical Co., Ltd. as Smancs (tradename); idarubicin fromPharmacia Corp. as Idamycin (tradename); sirolimus from Wyeth Corp. asRapamune (tradename); and valrubicin from Anthra Pharmaceuticals Inc. asValstar (tradename).

The above-mentioned plant-derived anticancer agents are commerciallyavailable, as exemplified by the following: vincristine from Shionogi &Co., Ltd. as Oncovin (tradename); vinblastine from Kyorin PharmaceuticalCo., Ltd. as Vinblastine (tradename); vindesine from Shionogi & Co.,Ltd. as Fildesin (tradename); etoposide from Nippon Kayaku Co., Ltd. asLastet (tradename); sobuzoxane from Zenyaku Kogyo Co., Ltd. as Perazolin(tradename); docetaxel from Aventis Corp. as Taxsotere (tradename);paclitaxel from Bristol-Myers Squibb Co. as Taxol (tradename); andvinorelbine from Kyowa Hakko Kogyo Co., Ltd. as Navelbine (tradename).

The above-mentioned anticancer platinum coordination compounds arecommercially available, as exemplified by the following: cisplatin fromNippon Kayaku Co., Ltd. as Randa (tradename); carboplatin fromBristol-Myers Squibb Co. as Paraplatin (tradename); nedaplatin fromShionogi & Co., Ltd. as Aqupla (tradename); and oxaliplatin fromSanofi-Synthelabo Co. as Eloxatin (tradename).

The above-mentioned anticancer camptothecin derivatives are commerciallyavailable, as exemplified by the following: irinotecan from YakultHonsha Co., Ltd. as Campto (tradename); topotecan from GlaxoSmithKlineCorp. as Hycamtin (tradename); and camptothecin from Aldrich ChemicalCo., Inc., U.S.A.

The above-mentioned anticancer tyrosine kinase inhibitors arecommercially available, as exemplified by the following: gefitinib fromAstraZeneca Corp. as Iressa (tradename); imatinib from Novartis AG asGleevec (tradename); and erlotinib from OSI Pharmaceuticals Inc. asTarceva (tradename).

The above-mentioned monoclonal antibodies are commercially available, asexemplified by the following: cetuximab from Bristol-Myers Squibb Co. asErbitux (tradename); bevacizumab from Genentech, Inc. as Avastin(tradename); rituximab from Biogen Idec Inc. as Rituxan (tradename);alemtuzumab from Berlex Inc. as Campath (tradename); and trastuzumabfrom Chugai Pharmaceutical Co., Ltd. as Herceptin (tradename).

The above-mentioned interferons are commercially available, asexemplified by the following: interferon α from Sumitomo PharmaceuticalCo., Ltd. as Sumiferon (tradename); interferon α-2a from TakedaPharmaceutical Co., Ltd. as Canferon-A (tradename); interferon α-2b fromSchering-Plough Corp. as Intron A (tradename); interferon β from MochidaPharmaceutical Co., Ltd. as IFNβ (tradename); interferon γ-1a fromShionogi & Co., Ltd. as Immunomax-γ(tradename); and interferon γ-n1 fromOtsuka Pharmaceutical Co., Ltd. as Ogamma (tradename).

The above-mentioned biological response modifiers are commerciallyavailable, as exemplified by the following: krestin from Sankyo Co.,Ltd. as krestin (tradename); lentinan from Aventis Corp. as Lentinan(tradename); sizofuran from Kaken Seiyaku Co., Ltd. as Sonifuran(tradename); picibanil from Chugai Pharmaceutical Co., Ltd. as Picibanil(tradename); and ubenimex from Nippon Kayaku Co., Ltd. as Bestatin(tradename).

The above-mentioned other anticancer agents are commercially available,as exemplified by the following: mitoxantrone from Wyeth Lederle Japan,Ltd. as Novantrone (tradename); L-asparaginase from Kyowa Hakko KogyoCo., Ltd. as Leunase (tradename); procarbazine from Nippon Roche Co.,Ltd. as Natulan (tradename); dacarbazine from Kyowa Hakko Kogyo Co.,Ltd. as Dacarbazine (tradename); hydroxycarbamide from Bristol-MyersSquibb Co. as Hydrea (tradename); pentostatin from Kagaku Oyobi KesseiRyoho Kenkyusho as Coforin (tradename); tretinoin from Nippon Roche Co.,Ltd. As Vesanoid (tradename); alefacept from Biogen Idec Inc. as Amevive(tradename); darbepoetin alfa from Amgen Inc. as Aranesp (tradename);anastrozole from AstraZeneca Corp. as Arimidex (tradename); exemestanefrom Pfizer Inc. as Aromasin (tradename); bicalutamide from AstraZenecaCorp. as Casodex (tradename); leuprorelin from Takeda PharmaceuticalCo., Ltd. as Leuplin (tradename); flutamide from Schering-Plough Corp.as Eulexin (tradename); fulvestrant from AstraZeneca Corp. as Faslodex(tradename); pegaptanib octasodium from Gilead Sciences, Inc. as Macugen(tradename); denileukin diftitox from Ligand Pharmaceuticals Inc. asOntak (tradename); aldesleukin from Chiron Corp. as Proleukin(tradename); thyrotropin alfa from Genzyme Corp. as Thyrogen(tradename); arsenic trioxide from Cell Therapeutics, Inc. as Trisenox(tradename); bortezomib from Millennium Pharmaceuticals, Inc. as Valcade(tradename); capecitabine from Hoffmann-La Roche, Ltd. as Xeloda(tradename); and goserelin from AstraZeneca Corp. as Zoladex(tradename).

The invention also relates to a method for the treatment of cancer,which comprises administering to a subject in need thereof atherapeutically-effective amount of the compound of the invention or itssalt or ester thereof.

In the process according to the invention, preferred therapeutic unitmay vary in accordance with, for example, the administration route ofthe compound of the invention, the type of the compound of the inventionused, and the dosage form of the compound of the invention used; thetype, administration route and dosage form of the other anticancer agentused in combination; and the type of cells to be treated, the conditionof patient, and the like. The optimal treatment under the givenconditions can be determined by a person skilled in the art, based onthe set conventional therapeutic unit and/or based on the content of thepresent specification.

In the process according to the invention, the therapeutic unit for thecompound of the invention may vary in accordance with, specifically, thetype of compound used, the type of compounded composition, applicationfrequency and the specific site to be treated, seriousness of thedisease, age of the patient, doctor's diagnosis, the type of cancer, orthe like. However, as an exemplary reference, the daily dose for anadult may be within a range of, for example, 1 to 1,000 mg in the caseof oral administration. In the case of parenteral administration,preferably intravenous administration, and more preferably intravenousdrip infusion, the daily dose may be within a range of, for example, 1to 100 mg/m² (body surface area). Here, in the case of intravenous dripinfusion, administration may be continuously carried out for, forexample, 1 to 48 hours. Moreover, the administration frequency may varydepending on the administering method and symptoms, but it is, forexample, once to five times a day. Alternatively, periodicallyintermittent administration such as administration every other day,administration every two days or the like may be employed as well in theadministering method. The period of withdraw from medication in the caseof parenteral administration is, for example, 1 to 6 weeks.

Although the therapeutic unit for the other anticancer agent used incombination with the compound of the invention is not particularlylimited, it can be determined, if needed, by those skilled in the artaccording to known literatures. Examples may be as follows.

The therapeutic unit of 5-fluorouracil (5-FU) is such that, in the caseof oral administration, for example, 200 to 300 mg per day isadministered in once to three times consecutively, and in the case ofinjection, for example, 5 to 15 mg/kg per day is administered once a dayfor the first 5 consecutive days by intravenous injection or intravenousdrip infusion, and then 5 to 7.5 mg/kg is administered once a day everyother day by intravenous injection or intravenous drip infusion (thedose may be appropriately increased or decreased).

The therapeutic unit of S-1 (Tegafur, Gimestat and Ostat potassium) issuch that, for example, the initial dose (singe dose) is set to thefollowing standard amount in accordance with the body surface area, andit is orally administered twice a day, after breakfast and after dinner,for 28 consecutive days, followed by withdrawal from medication for 14days. This is set as one course of administration, which is repeated.The initial standard amount per unit body surface area (Tegafurequivalent) is 40 mg in one administration for an area less than 1.25m²; 50 mg in one administration for an area of 1.25 m² to less than 1.5m²; 60 mg in one administration for an area of 1.5 m² or more. This doseis appropriately increased or decreased depending on the condition ofthe patient.

The therapeutic unit for gemcitabine is, for example, 1 g asgemcitabine/m² in one administration, which is administered byintravenous drip infusion over a period of 30 minutes, and oneadministration per week is continued for 3 weeks, followed by withdrawalfrom medication on the fourth week. This is set as one course ofadministration, which is repeated. The dose is appropriately decreasedin accordance with age, symptom or development of side-effects.

The therapeutic unit for doxorubicin (e.g., doxorubicin hydrochloride)is such that, for example, in the case of intravenous injection, 10 mg(0.2 mg/kg) (titer) is administered once a day by intravenous one-shotadministration for 4 to 6 consecutive days, followed by withdrawal frommedication for 7 to 10 days. This is set as one course ofadministration, which is repeated two or three times. Here, the totaldose is preferably 500 mg (titer)/m² (body surface area) or less, and itmay be appropriately increased or decreased within the range.

The therapeutic unit for etoposide is such that, for example, in thecase of intravenous injection, 60 to 100 mg/m² (body surface area) perday is administered for 5 consecutive days, followed by withdrawal frommedication for three weeks (the dose may be appropriately increased ordecreased). This is set as one course of administration, which isrepeated. Meanwhile, in the case of oral administration, for example,175 to 200 mg per day is administered for 5 consecutive days, followedby withdrawal from medication for three weeks (the dose may beappropriately increased or decreased). This is set as one course ofadministration, which is repeated.

The therapeutic unit for docetaxel (docetaxel hydrate) is such that, forexample, 60 mg as docetaxel/m² (body surface area) is administered oncea day by intravenous drip infusion over a period of 1 hour or longer atan interval of 3 to 4 weeks (the dose may be appropriately increased ordecreased).

The therapeutic unit of paclitaxel is such that, for example, 210 mg/m²(body surface area) is administered once a day by intravenous dripinfusion over a period of 3 hours, followed by withdrawal frommedication for at least 3 weeks. This is set as one course ofadministration, which is repeated. The dose may be appropriatelyincreased or decreased.

The therapeutic unit for cisplatin is such that, for example, in thecase of intravenous injection, 50 to 70 mg/m² (body surface area) isadministered once a day; followed by withdrawal from medication for 3weeks or longer (the dose may be appropriately increased or decreased).This is set as one course of administration, which is repeated.

The therapeutic unit for carboplatin is such that, for example, 300 to400 mg/m² is administered once a day by intravenous drip infusion over aperiod of 30 minutes or longer, followed by withdrawal from medicationfor at least 4 weeks (the dose may be appropriately increased ordecreased). This is set as one course of administration, which isrepeated.

The therapeutic unit for oxaliplatin is such that 85 mg/m² isadministered once a day by intravenous injection, followed by withdrawalfrom medication for two weeks. This is set as one course ofadministration, which is repeated.

The therapeutic unit for irinotecan (e.g., irinotecan hydrochloride) issuch that, for example, 100 mg/m² is administered once a day byintravenous drip infusion for 3 or 4 times at an interval of one week,followed by withdrawal from medication for at least two weeks.

The therapeutic unit for topotecan is such that, for example, 1.5 mg/m²is administered once a day by intravenous drip infusion for 5 days,followed by withdrawal from medication for at least 3 weeks.

The therapeutic unit for cyclophosphamide is such that, for example, inthe case of intravenous injection, 100 mg is administered once a day byintravenous injection for consecutive days. If the patient can tolerate,the daily dose may be increased to 200 mg. The total dose is 3,000 to8,000 mg, which may be appropriately increased or decreased. Ifnecessary, it may be injected or infused intramuscularly,intrathoracically or intratumorally. On the other hand, in the case oforal administration, for example, 100 to 200 mg is administered a day.

The therapeutic unit for gefitinib is such that 250 mg is orallyadministered once a day.

The therapeutic unit for cetuximab is such that, for example, 400 mg/m²is administered on the first day by intravenous drip infusion, and then250 mg/m² is administered every week by intravenous drip infusion.

The therapeutic unit for bevacizumab is such that, for example, 3 mg/kgis administered every week by intravenous drip infusion.

The therapeutic unit for trastuzumab is such that, for example,typically for an adult, once a day, 4 mg as trastuzumab/kg (body weight)is administered initially, followed by intravenous drip infusion of 2mg/kg over a period of 90 minutes or longer every week from the secondadministration.

The therapeutic unit for exemestane is such that, for example, typicallyfor an adult, 25 mg is orally administered once a day after meal.

The therapeutic unit for leuprorelin (e.g., leuprorelin acetate) is suchthat, for example, typically for an adult, 11.25 mg is subcutaneouslyadministered once in 12 weeks.

The therapeutic unit for imatinib is such that; for example, typicallyfor an adult in the chronic phase of chronic myelogenous leukemia, 400mg is orally administered once a day after meal.

The therapeutic unit for a combination of 5-FU and leucovorin is suchthat, for example, 425 mg/m² of 5-FU and 200 mg/m² of leucovorin areadministered from the first day to the fifth day by intravenous dripinfusion, and this course is repeated at an interval of 4 weeks.

The invention is described more concretely with reference to thefollowing Examples and Production Examples, which, however, are notintended to restrict the scope of the invention.

In thin-layer chromatography in Examples and Production Examples, Silicagel₆₀F₂₅₄ (Merck) was used for the plate, and a UV detector was used fordetection. Wakogel™ C-300 or C-200(Wako Pure Chemical Industries) or NH(Fuji Silysia Chemical) was used for column silica gel. In MSspectrometry, used was JMS-SX102A (JEOL) or QUATTROII (Micromass). InNMR spectrometry, dimethylsulfoxide was used as the internal standard ina heavy dimethylsulfoxide solution; a spectrometer of Gemini-300 (300MHz; Varian), VXR-300 (300 MHz; Varian), Mercury 400 (400 MHz; Varian)or Inova 400(400 MHz; Varian) was used; and all 8 values are by ppm.

The meanings of the abbreviations in NMR are mentioned below.

-   -   s: singlet    -   d: doublet    -   dd: double doublet    -   t: triplet    -   dt: double triplet    -   q: quartet    -   m: multiplet    -   br: broad    -   J: coupling constant    -   Hz: hertz    -   DMSO-d₆: heavy dimethylsulfoxide

PRODUCTION EXAMPLE 1 Production of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Tert-butyl 1-allylhydrazinecarboxylate

250 g of tert-butyl hydrazinecarboxylate was added to toluene (3 L)solution of 280 g of phthalic anhydride. Using a Dean-Stark waterseparator, the reaction mixture was heated under reflux for 3 hours.This was cooled to room temperature, the formed solid was taken outthrough filtration to obtain 516 g of crude tert-butyl(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)carbamate.

520 g of potassium carbonate, 43.3 g of benzyltriethylammonium chlorideand 250 mL of allyl bromide were added in that order to acetonitrile(3.5 L) solution of the above compound, and stirred at room temperaturefor 18 hours. 1.5 L of water was added to the reaction solution, and theacetonitrile layer was separated and concentrated. One L of water wasadded to the residue and the aqueous layer, extracted with ethylacetate, and the ethyl acetate layer was washed with saturated salinewater, and then dried with anhydrous sodium sulfate. The solvent wasevaporated away under reduced pressure, and the precipitated colorlesssolid was washed with hexane and dried to obtain 460 g of crudetert-butyl allyl(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)carbamate.

With cooling in an ice bath, 100 mL of methylhydrazine was added totetrahydrofuran (3.0 L) solution of the above compound, then restored toroom temperature, and stirred for 18 hours. The precipitated insolublematter was taken out through filtration, and the filtrate wasconcentrated. A mixed solvent of hexane/ethyl acetate (3/1) was added tothe residue, and the precipitated insoluble matter was taken out throughfiltration. This operation was repeated five times, then the filtratewas concentrated under reduced pressure, the resulting residue wasdistilled under reduced pressure to obtain 211 g of the entitledcompound as a pale yellow oily substance.

ESI-MS Found: m/z [M+H]+ 173.4.

2) Production of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

260 mL of N,N-diisopropylethylamine and 106 g of the hydrazine obtainedin the above 1 were added to tetrahydrofuran (1.5 L) solution of 142 gof ethyl 4-chloro-2-(methylthio)pyridine-5-carboxylate, and stirred withheating under reflux for 18 hours. After cooled to room temperature, thereaction solution was evaporated under reduced pressure, and 500 mL ofdiethyl ether was added to the residue, and the precipitated solid wasseparated through filtration. The filtrate was evaporated under reducedpressure, the residue was cooled in an ice bath, 400 mL oftrifluoroacetic acid was gradually added thereto, and stirred at roomtemperature for 1 hour and then at 70° C. for 1 hour. The reactionsolution was evaporated under reduced pressure, 500 mL of ethanol wasadded thereto and cooled in an ice bath, and 1.0 L of 6 N sodiumhydroxide solution was added thereto and stirred at room temperature for15 minutes. Cooled in an ice bath, the reaction solution was made acidicwith 400 mL of concentrated hydrochloric acid, and then evaporated underreduced pressure. The residue was partitioned in chloroform and water,and the chloroform layer was extracted, washed with saturated salinewater, and dried with anhydrous sodium sulfate. The solvent wasevaporated away under reduced pressure, and the formed yellow solid wastaken out through filtration, washed with ethanol and diethyl ether, anddried to obtain 99.1 g of the entitled compound as a yellow solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.66 (1.0H, brs), 5.83 (1.0H, ddt, J=17.1,9.8, 5.4 Hz), 5.13 (1.0H, d, J=9.8 Hz), 5.06 (1.0H, d, J=17.1 Hz), 4.34(2.011, d, J=5.4 Hz), 2.51 (3.0H, s).

ESI-MS Found: m/z [M+H]+ 223.3.

PRODUCTION EXAMPLE 2 Production of2-(2-chlorophenyl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of ethyl4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate

At room temperature, 16.2 mL of N,N-diisopropylethylamine was added totetrahydrofuran (300 mL) solution of 9.4 g of ethyl4-chloro-2-(methylthio)pyrimidine-5-carboxylate and 8.3 g of2-chlorophenylhydrazine hydrochloride, and heated under reflux for 18hours. The solvent was concentrated under reduced pressure, water wasadded to this, and extracted with ethyl acetate, and the ethyl acetatelayer was washed with saturated saline water, and dried with anhydroussodium sulfate. The solvent was evaporated away under reduced pressureto obtain crude ethyl4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylateas a yellow oily substance.

2) Production of2-(2-chlorophenyl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

50 mL of aqueous 5 N sodium hydroxide solution was added to methanol(100 mL)-tetrahydrofuran (100 mL) solution of 13.8 g of the compoundobtained in the above 1, and stirred at room temperature for 3 hours.The reaction system was concentrated under reduced pressure, the residuewas made acidic with aqueous 5 N hydrochloric acid added thereto, andthen extracted with a mixed solvent of 2-propanol/chloroform (20/80).The solvent was evaporated away under reduced pressure to obtain crude4-[2-(2-chlorophenyl)hydrazino]-2-(methylthio)pyrimidine-5-carboxylicacid as a white solid.

500 mL of toluene and 60 mL of thionyl chloride were added to the abovecompound, and heated under reflux for 1 hour. The solvent was evaporatedaway under reduced pressure, Water was added to the residue, extractedwith a mixed solvent of 2-propanol/chloroform (20/80), and dried withanhydrous sodium sulfate. The solvent was evaporated away under reducedpressure to obtain 5.8 g of the entitled compound as a yellow solid.

¹HNMR (400 MHz, DMSO-d₆) δ: 8.78 (1H, s), 7.44-7.77 (4H, m), 2.56 (3H,s).

APCI-MS Found: m/z [M+H]+ 293.0.

PRODUCTION EXAMPLE 3 Production of2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of ethyl 4-hydrazino-2-(methylthio)pyrimidine-5-carboxylate

9.71 g of hydrazine monohydrate was dissolved in 200 mL of ethanol, andcooled to 0° C. To this was added a solution prepared by dissolving 15.0g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate in 200 mL ofethanol, and stirred for 1 hour. The precipitated solid was taken outthrough filtration, washed with distilled water, and dried to obtain9.66 g of the entitled compound as a white solid.

¹H-NMR (400 MHz, CD₃OD) δ: 8.56 (1H, s), 4.36 (2H, q, J=7.2 Hz), 2.62(3H, s), 1.39 (3H, t, J=7.2 Hz).

ESI-MS Found: m/z [M+H]+ 229.

2) Production of ethyl4-[2-(1-methylethylidene)hydrazino]-2-(methylthio)pyrimidine-5-carboxylate

9.66 g of the above compound was dissolved in 300 mL of acetone, andstirred at 70° C. for 12 hours. The reaction solution was cooled to roomtemperature, and the solvent was evaporated away under reduced pressureto obtain 9.66 g of the entitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.75 (1H, s), 4.36 (2H, q, J=6.8 Hz), 2.60(3H, s), 2.17 (3H, s), 2.04 (3H, s), 1.40 (3H, t, J=6.8 Hz).

ESI-MS Found: m/z [M+H]+ 269.

3) Production of ethyl4-(2-isopropylhydrazino)-2-(methylthio)pyrimidine-5-carboxylate

9.66 g of the above compound was dissolved in 180 mL of methanol, andcooled to 0° C. Methanol (36 mL) solution of 2.26 g of sodiumcyanoborohydride and 0.15 mL of concentrated hydrochloric acid wereadded to the reaction solution, and stirred for 30 minutes. Aqueoussaturated sodium hydrogencarbonate solution was added to the reactionsolution, and extracted with ethyl acetate. This was dried withanhydrous sodium sulfate, and the solvent was evaporated away underreduced pressure to obtain 10.2 g of the entitled compound as a yellowamorphous substance.

¹H-NMR (400 MHz, CDCl₃) δ: 9.39 (1H, s), 8.62 (1H, s), 4.34 (2H, q,J=7.2 Hz), 3.24 (1H, septet, J=6.3 Hz), 2.56 (4H, t, J=17.1 Hz), 1.37(4H, t, J=7.1 Hz), 1.14 (7H, d, J=6.3 Hz).

ESI-MS Found: m/z [M+H]+ 271.

4) Production of2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

300 mL of aqueous 5 N sodium hydroxide solution was added to methanol(100 mL) solution of 10.2 g of the above compound, and stirred for 3hours. Methanol was evaporated away under reduced pressure, aqueous 5 Nhydrochloric acid solution was added to the residue to make it have a pHof about 2, and then stirred for 3.5 hours. The reaction solution wasextracted with chloroform, washed with saturated saline water, and driedwith anhydrous sodium sulfate. The solvent was evaporated away underreduced pressure to obtain 7.52 g of the entitled compound as an orangeamorphous substance.

¹H-NMR (400 MHz, CDCl₃) δ: 8.71 (1H, s), 4.85 (1H, septet, J=6.8, 6.8Hz), 2.60 (3H, s), 1.44 (6H, d, J=6.8 Hz).

ESI-MS Found: m/z [M+H]+ 225.

PRODUCTION EXAMPLE 4 Production of6-(methylthio)-1-phenyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

60 mL of triethylamine was added to tetrahydrofuran (200 mL) solution of25 g of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate and 12.7mL of phenylhydrazine, and stirred at room temperature for 18 hours. Thesolvent was concentrated under reduced pressure, water was added to theresidue, then washed with ether, and made acidic with aqueous 5 Nhydrochloric acid solution added thereto. The precipitated solid wastaken out through filtration, and washed with water and 2-propanol toobtain 10.8 g of the entitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 12.18 (1H, s), 9.02 (1H, s), 8.13 (2H, dd,J=8.8, 1.0 Hz), 7.52 (2H, td, J=7.1, 1.6 Hz), 7.26 (1H, tt, J=7.1, 1.0Hz), 2.61 (3H, s).

ESI-MS Found: m/z [M+H]+ 259.1.

PRODUCTION EXAMPLE 5 Production of[5-amino-2-(4-ethylpiperazin-1-yl)phenyl]methanol 1) Production of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol

4.24 g of potassium carbonate was added to N-methylpyrrolidone (4.24 mL)solution of 4.24 g of 2-fluoro-5-nitrobenzyl alcohol and 4.24 g ofN-ethylpiperazine, and stirred at 140° C. for 14 hours. Water was addedto the reaction liquid, and extracted with ethyl acetate. The organiclayer was washed with water and saturated saline water in that order,then dried with anhydrous magnesium sulfate, and the solvent wasevaporated away under reduced pressure. The crude product was purifiedthrough silica gel column chromatography (hexane/ethyl acetate) toobtain the entitled compound as a yellow solid.

2) Production of [5-amino-2-(4-ethylpiperazin-1-yl)phenyl]methanol

7.0 g of iron and 15 g of ammonium chloride were added to ethanol/water(1/1, 80 mL) solution of the compound obtained in the above reaction,and heated under reflux for 1 hour. The reaction liquid was concentratedunder reduced pressure, and made basic with aqueous 5 N sodium hydroxidesolution added thereto. This was extracted with chloroform/isopropanol(80/20), the organic layer was dried with anhydrous magnesium sulfate,and the solvent was evaporated away to obtain 2.49 g of the entitledcompound.

¹H-NMR (400 MHz, CDCl₃) δ: 8.27 (1H, d, J=2.4 Hz), 8.14 (1H, dd, J=8.8,2.9 Hz), 7.16 (1H, d, J=9.3 Hz), 4.80 (2H, s), 3.10 (4H, t, J=4.9 Hz),2.66 (4H, brs), 2.51 (2H, q, J=7.3 Hz), 1.14 (3H, t, J=7.1 Hz).

ESI-MS Found: m/z [M+H]+ 235.

PRODUCTION EXAMPLE 6 Production of4-[4-(2-ethoxyethyl)piperazin-1-yl]-3-methylaniline 1) Production of1-(2-ethoxyethyl)-4-(2-methyl-4-nitrophenyl)piperazine

In the same manner as in Production Example 5-1, but using4-(2-ethoxyethyl)piperazine in place of N-ethylpiperazine used inProduction Example 5-1, using 4-nitrofluorobenzene in place of2-fluoro-5-nitrobenzyl alcohol, and using dimethylsulfoxide in place ofN-methylpyrrolidone, 1.50 g of the entitled compound was obtained as ayellow solid.

2) Production of 4-[4-(2-ethoxyethyl)piperazin-1-yl]-3-methylaniline

In the same manner as in Production Example 5-2, but using1-(2-ethoxyethyl)-4-(2-methyl-4-nitrophenyl)piperazine in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, 1.01 g of the entitled compound was obtained as a whitesolid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 6.66 (2H, dd, J=6.6, 2.2 Hz), 6.47 (2H, dd,J=6.6, 2.2 Hz), 4.57 (2H, s), 3.48 (2H, t, J=5.9 Hz), 3.42 (2H, q, J=7.0Hz), 2.88 (4H, t, J=4.9 Hz), 2.55-2.47 (6H, m), 1.10 (3H, t, J=7.0 Hz).

ESI-MS Found: m/z [M+H]+ 250.

PRODUCTION EXAMPLE 7 Production of4-[4-(2-hydroxyethyl)piperazin-1-yl]-3-methylaniline 1) Production of1-(2-hydroxyethyl)-4-(2-methyl-4-nitrophenyl)piperazine

In the same manner as in Production Example 5-1, but using4-(2-ethoxyethyl)piperazine in place of N-ethylpiperazine used inProduction Example 5-1, using 5-nitro-2-fluorotoluene in place of2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in placeof potassium carbonate, and using dimethylsulfoxide in place ofN-methylpyrrolidone, the entitled compound was obtained as a yellowsolid.

2) Production of 4-[4-(2-hydroxyethyl)piperazin-1-yl]-3-methylaniline

In the same manner as in Production Example 5-2, but using1-(2-hydroxyethyl)-4-(2-methyl-4-nitrophenyl)piperazine in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, the entitled compound was obtained as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 6.73 (1H, d, J=8.3 Hz), 6.37 (1H, d, J=2.4Hz), 6.33 (1H, dd, J=8.3, 2.4 Hz), 4.63 (2H, s), 4.38 (1H, t, J=5.4 Hz),3.50 (2H, q, J=6.3 Hz), 2.67 (411, t, J=4.6 Hz), 2.53-2.48 (4H, m), 2.41(2H, t, J=6.3 Hz), 2.09 (3H, s).

ESI-MS Found: m/z [M+H]+ 236.

PRODUCTION EXAMPLE 8 Production of4-[4-(cyclopropylmethyl)piperazin-1-yl]-3-methylaniline 1) Production of1-(cyclopropylmethyl)-4-(2-ethyl-4-nitrophenyl)piperazine

In the same manner as in Production Example 5-1, but using4-(cyclopropylmethyl)piperazine in place of N-ethylpiperazine used inProduction Example 5-1, using 2-fluoro-5-nitrotoluene in place of2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in placeof potassium carbonate, and using dimethylsulfoxide in place ofN-methylpyrrolidone, 280 mg of the entitled compound was obtained as ayellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.02 (1H, s), 8.03 (1H, d, J=8.7 Hz), 6.99(1H, d, J=8.7 Hz), 3.04-3.10 (4H, m), 2.67-2.751 (4H, m), 2.3.6 (3H, s),2.33 (2H, s), 0.82-0.97 (1H, m), 0.51-0.58 (2H, m), 0.11-0.17 (2H, m).

2) Production of 4-[4-(cyclopropylmethyl)piperazin-1-yl]-3-methylaniline

In the same manner as in Production Example 5-2, but using1-(cyclopropylmethyl)-4-(2-methyl-4-nitrophenyl)piperazine in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, 230 mg of the entitled compound was obtained as a whitesolid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 6.67 (1H, d, J=8.3 Hz), 6.30 (1H, d, J=2.4Hz), 6.26 (1H, dd, J=8.3, 2.4 Hz), 4.55 (2H, s), 2.61 (4H, t, J=4.4 Hz),2.51-2.38 (4H, m), 2.12 (2H, d, J=6.8 Hz), 2.02 (3H, s), 0.79-0.71 (1H,m), 0.41-0.35 (2H, m), 0.02-0.03 (2H, m).

ESI-MS Found: m/z [M+H]+ 246.

PRODUCTION EXAMPLE 9 Production of4-(4-cyclopropylpiperazin-1-yl)-3-methyl aniline 1) Production of1-(2-methyl-4-nitrophenyl)piperazine hydrochloride

In the same manner as in Production Example 5-1, but using tert-butylpiperazine-1-carboxylate in place of N-ethylpiperazine used inProduction Example 5-1, using 2-fluoro-5-nitrotoluene in place of2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in placeof potassium carbonate, and using dimethylsulfoxide in place ofN-methylpyrrolidone, 4.91 g of crude tert-butyl4-[2-methyl-4-nitrophenyl]piperazine-1-carboxylate was obtained as ayellow solid.

4 N hydrochloric acid/ethyl acetate solution was added to methanol (50mL) solution of the compound obtained in the above reaction, and stirredat room temperature for 30 minutes. The reaction liquid was concentratedunder reduced pressure to obtain 3.86 g of crude4-(2-methyl-4-nitrophenyl)piperazine hydrochloride.

2) Production of 1-cyclopropyl-4-(2-methyl-4-nitrophenyl)piperazine

0.777 mL of [(1-ethoxycyclopropyl)-oxy]trimethylsilane, 244 mg of sodiumcyanoborohydride and 0.1 mL of acetic acid were added to methanol (20mL) solution of 500 mg of the compound obtained in Production Example9-1, and stirred at room temperature for 15 hours. The reaction liquidwas concentrated under reduced pressure, and the residue was made basicwith aqueous 2 N sodium hydroxide solution added thereto. This wasextracted with chloroform, the organic layer was dried with anhydrousmagnesium sulfate, and the solvent was evaporated away. The crudeproduct was purified through silica gel column chromatography(hexane/ethyl acetate) to obtain 441 mg of the entitled compound as ayellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.03 (1H, s), 8.02 (1H, d, J=8.8 Hz), 6.97(1H, d, J=8.8 Hz), 2.96-3.03 (4H, m), 2.76-2.81 (4H, m), 2.36 (3H, s),1.66-1.73 (1H, m), 0.42-0.50 (4H, m).

ESI-MS Found: m/z [M+H]+ 262.

3) Production of 4-(4-cyclopropylpiperazin-1-yl)-3-methylaniline

In the same manner as in Production Example 5-2, but using1-cyclopropyl-4-(2-methyl-4-nitrophenyl)piperazine in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, 326 mg of the entitled compound was obtained as a whitesolid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 6.41 (1H, d, J=8.3 Hz), 6.07 (1H, d, J=2.4Hz), 6.02 (1H, dd, J=8.3, 2.4 Hz), 4.33 (2H, s), 2.37-2.28 (4H, m),2.21-2.17 (4H, m), 1.80 (3H, s), 1.36-1.31 (1H, m), 0.11 (2H, td, J=6.3,4.1 Hz), 0.01-0.03 (2H, m).

ESI-MS Found: m/z [M+H]+ 232.

PRODUCTION EXAMPLE 10 Production of[5-amino-2-(4-cyclopropylpiperazin-1-yl)phenyl]methanol 1) Production of(5-nitro-2-piperazin-1-ylphenyl)methanol hydrochloride

In the same manner as in Production Example 5-1, but using tert-butylpiperazine-1-carboxylate in place of N-ethylpiperazine used inProduction Example 5-1, using N,N-diisopropylethylamine in place ofpotassium carbonate, and using dimethylsulfoxide in place ofN-methylpyrrolidone, 5.6 g of crude tert-butyl4-[2-(hydroxymethyl)-4-nitrophenyl]piperazine-1-carboxylate was obtainedas a yellow solid.

4 N hydrochloric acid/ethyl acetate solution was added to methanol (50mL) solution of 5.6 g of the compound obtained in the above reaction,and stirred at room temperature for 30 minutes. The reaction liquid wasconcentrated under reduced pressure to obtain 4.5 g of crude(5-nitro-2-piperazin-1-ylphenyl)methanol hydrochloride as a white solid.

2) Production of [2-(4-cyclopropylpiperazin-1-yl)-5-nitrophenyl]methanol

In the same manner as in Production Example 9-2, but using(5-nitro-2-piperazin-1-ylphenyl)methanol in place of4-(2-methyl-4-nitrophenyl)piperazine hydrochloride used in ProductionExample 9-2, 0.4 g of the entitled compound was obtained as a yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.26 (1H, d, J=2.9 Hz), 8.13 (1H, dd, J=8.8,2.9 Hz), 7.14 (1H, d, J=8.8 Hz), 4.81 (2H, s), 3.45 (1H, s), 3.07-3.00(4H, m), 2.87-2.78 (4H, m), 1.76-1.69 (1H, m), 0.56-0.40 (4H, m).

3) Production of 5-amino-2-(4-cyclopropylpiperazin-1-yl)phenyl]methanol

In the same manner as in Production Example 5-2, but using[2-(4-cyclopropylpiperazin-1-yl)-5-nitrophenyl]methanol in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, 340 mg of the entitled compound was obtained as a whitesolid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 6.47 (1H, d, J=8.3 Hz), 6.35 (1H, d, J=2.4Hz), 6.07 (1H, dd, J=8.3, 2.4 Hz), 4.65 (1H, t, J=5.6 Hz), 4.44 (2H, s),4.16 (2H, d, J=5.6 Hz), 2.37-2.27 (4H, m), 2.20-2.19 (4H, m), 1.36-1.32(1H, m), 0.11 (2H, td, J=6.2, 4.2 Hz), 0.01-0.02 (2H, m).

ESI-MS Found: m/z [M+H]+ 248.

PRODUCTION EXAMPLE 11 Production of4-(4-isopropylpiperazin-1-yl)-3-methylaniline 1) Production of1-isopropyl-4-(2-methyl-4-nitrophenyl)piperazine

1.13 g of acetone and 183 mg of sodium cyanoborohydride were added toethanol (20 mL) solution of 500 mg of the compound obtained inProduction Example 9-1, and stirred at room temperature for 15 hours.The reaction liquid was concentrated under reduced pressure, and madebasic with aqueous 2 N sodium hydroxide solution added thereto. This wasextracted with chloroform, the organic layer was dried with anhydrousmagnesium sulfate, and the solvent was evaporated away. The crudeproduct was purified through silica gel column chromatography(hexane/ethyl acetate) to obtain 120 mg of the entitled compound as ayellow solid.

2) Production of 4-(4-isopropylpiperazin-1-yl)-3-methylaniline

In the same manner as in Production Example 5-2, but using1-isopropyl-4-(2-methyl-4-nitrophenyl)piperazine in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, 91 mg of the entitled compound was obtained as a whitesolid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 6.73 (1.0H, d, J=8.3 Hz), 6.37 (1.0H, d,J=2.4 Hz), 6.32 (1.0H, dd, J=8.3, 2.4 Hz), 4.62 (2.0H, s), 2.66 (4.0H,t, J=4.9 Hz), 2.66-2.60 (1.0H, m), 2.54-2.47 (4.0H, m), 2.09 (3.0H, s),0.98 (6.0H, d, J=6.3 Hz).

ESI-MS Found: m/z [M+H]+ 234.

PRODUCTION EXAMPLE 12 Production of{5-amino-2-[4-(methoxyacetyl)piperazin-1-yl]phenyl}methanol 1)Production of{2-[4-(methoxyacetyl)piperazin-1-yl]-5-nitrophenyl}methanol

0.167 mL of methoxyacetyl chloride and 506 mg of potassium carbonatewere added to tetrahydrofuran (20 mL)-N,N-dimethylformamide (5 mL)solution of 500 mg of the compound obtained in Production Example 9-1,and stirred at room temperature for 2 hours. Water was added to thereaction liquid, extracted with chloroform, and the organic layer wasdried with anhydrous magnesium sulfate. The solvent was evaporated awayto obtain 135 mg of crude{2-[4-(methoxyacetyl)piperazin-1-yl]-5-nitrophenyl}methanol as a yellowsolid.

2) Production of{5-amino-2-[4-(methoxyacetyl)piperazin-1-yl]phenyl}methanol

In the same manner as in Production Example 5-2, but using{2-[4-(methoxyacetyl)piperazin-1-yl]-5-nitrophenyl}methanol in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, the entitled compound was obtained as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 6.76 (1.0H, d, J=8.3 Hz), 6.67 (1.0H, d,J=2.4 Hz), 6.38 (1.0H, dd, J=8.3, 2.4 Hz), 4.89 (1.0H, t, J=5.6 Hz),4.79 (2.0H, s), 4.48 (2.0H, d, J=5.6 Hz), 4.09 (2.0H, s), 3.54-3.41(4.0H, m), 3.28 (3.0H, s), 2.70-2.62 (4.0H, m).

ESI-MS Found: m/z [M+H]+ 280.

PRODUCTION EXAMPLE 13 Production of4-{4-[2-(methylsulfonyl)ethyl]piperazin-1-yl}aniline] 1) Production of1-(4-nitrophenyl)piperazine hydrochloride

In the same manner as in Production Example 9-1, but using4-fluoronitrobenzene in place of 2-fluoro-5-nitrotoluene used inProduction Example 9-1, 4.33 g of crude 4-(4-nitrophenyl)piperazinehydrochloride was obtained.

2) Production of 1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperazine

0.49 mL of methylvinyl sulfone and 0.5 mL of N,N-diisopropylethylaminewere added to ethanol (10 mL) solution of 458 mg of the compoundobtained in Production Example 13-1, and stirred at room temperature for15 hours. Aqueous saturated sodium hydrogencarbonate solution was addedto the reaction liquid, and extracted three times with ethyl acetate.The organic layer was washed with saturated saline water, and dried withanhydrous magnesium sulfate. The solvent was evaporated away to obtaincrude 1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperazine.

3) Production of 4-{4-[2-(methylsulfonyl)ethyl]piperazin-1-yl}aniline

200 mg of 10% palladium-carbon was added to methanol (20 mL) solution ofthe compound obtained in Production Example 13-2, and stirred inone-atmospheric hydrogen atmosphere at room temperature for 4 hours.Palladium-carbon was removed through filtration, and the filtrate wasconcentrated under reduced pressure to obtain 611 mg of the entitledcompound.

¹H-NMR (400 MHz, DMSO-d₆) δ: 6.67 (2H, d, J=8.8 Hz), 6.47 (2H, d, J=8.8Hz), 4.64 (2H, s), 3.35-3.28 (4H, m), 3.02 (2H, s), 2.92 (3H, s),2.91-2.86 (4H, m), 2.72 (2H, t, J=6.6 Hz), 2.53 (4H, t, J=4.6 Hz).

ESI-MS Found: m/z [M+H]+ 284.

PRODUCTION EXAMPLE 14 Production of4-(1,1-dioxidothiomorpholin-4-yl)-3-methylaniline 1) Production of4-(2-methyl-4-nitrophenyl)thiomorpholine 1,1-dioxide

In the same manner as in Production Example 5-1, but usingthiomorpholine in place of N-ethylpiperazine used in Production Example5-1, using 5-nitro-2-fluorotoluene in place of 2-fluoro-5-nitrobenzylalcohol, using N,N-diisopropylethylamine in place of potassiumcarbonate, and using dimethylsulfoxide in place of N-methylpyrrolidone,crude 4-(2-methyl-4-nitrophenyl)thiomorpholine was obtained.

19 g of m-chloroperbenzoic acid was added to chloroform (100 mL)solution of the compound obtained in the above reaction, and stirredwith cooling with ice for 24 hours. The reaction liquid was washed withaqueous sodium sulfite solution and aqueous saturated sodiumhydrogencarbonate solution in that order, and dried with anhydroussodium sulfate. The solvent was evaporated away under reduced pressureto obtain 4.85 g of the entitled compound.

2) Production of 4-(1,1-dioxidothiomorpholin-4-yl)-3-methylaniline

In the same manner as in Production Example 13-3, but using4-(2-methyl-4-nitrophenyl)thiomorpholine 1,1-dioxide in place of1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperazine used inProduction Example 13-3, 1.01 g of the entitled compound was obtained asa white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 10.08-9.87 (2H, m), 7.19 (1H, d, J=8.3 Hz),7.14-7.10 (1H, m), 7.13 (1H, s), 3.26 (8H, s), 2.28 (3H, s).

ESI-MS Found: m/z [M+H]+ 241.

PRODUCTION EXAMPLE 15 Production of4-[2-(dimethylamino)ethoxy]-3-methylaniline 1) Production ofN,N-dimethyl-2-(2-methyl-4-nitrophenoxy)ethylamine

Acetonitrile (30 mL) solution of 2 g of 2-methyl-4-nitrophenol, 1.87 gof 2-dimethylaminoethyl chloride and 5.4 g of potassium carbonate wasstirred at 120° C. for 23 hours. The reaction liquid was concentratedunder reduced pressure, and the residue was dissolved in ethyl acetate.The organic layer was washed with water, and dried with anhydrous sodiumsulfate. The solvent was evaporated away under reduced pressure, and thecrude product was purified through silica gel column chromatography(chloroform/methanol) to obtain 600 mg of the entitled compound as awhite solid.

2) Production of 4-[2-(dimethylamino)ethoxy]-3-methylaniline

In the same manner as in Production Example 13-3, but usingN,N-dimethyl-2-(2-methyl-4-nitrophenoxy)ethylamine in place of1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperazine used inProduction Example 13-3, 542 mg of the entitled compound was obtained asa white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 6.60 (1H, d, J=8.5 Hz), 6.34 (1H, d, J=2.4Hz), 6.29 (1H, dd, J=8.5, 2.4 Hz), 3.98 (2H, t, J=5.6 Hz), 2.98 (2H, t,J=5.6 Hz), 2.49 (6H, s), 2.00 (3H, s).

ESI-MS Found: m/z [M+H]+ 195.

PRODUCTION EXAMPLE 16 Production of4-[2-(dimethylamino)ethoxy]-3,5-dimethylaniline 1) Production of2-(2,6-dimethyl-4-nitrophenoxy)-N,N-dimethylethylamine

3.4 mL of diisopropyl azodicarboxylate was added to 1.9 g of2,6-dimethyl-4-nitrophenol and 1.71 mL of 2-dimethylaminoethanol, andstirred at room temperature for 16 hours. The reaction liquid wasdiluted with ethyl acetate, and the organic layer was extracted with 2 Nhydrochloric acid. The aqueous layer was made basic with aqueous 2 Nsodium hydroxide solution, and then extracted with ethyl acetate. Theorganic layer was dried with anhydrous sodium sulfate, and the solventwas evaporated away under reduced pressure to obtain 667 mg of theentitled compound.

2) Production of 4-[2-(dimethylamino)ethoxy]-3,5-dimethylaniline

In the same manner as in Production Example 13-3, but using2-(2,6-dimethyl-4-nitrophenoxy)-N,N-dimethylethylamine in place of1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperazine used inProduction Example 13-3, 305 mg of the entitled compound was obtained asa white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 6.19 (2H, s), 3.88 (2H, t, J=4.9 Hz),3.40-3.23 (2H, m), 3.25 (2H, t, J=4.9 Hz), 2.72 (6H, s), 2.09 (6H, s).

ESI-MS Found: m/z [M+H]+ 209.

PRODUCTION EXAMPLE 17 Production of3-methyl-4-(1-methyl-1H-pyrazol-4-yl)aniline 1) Production of1-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrazole

5 mL of aqueous 2 M sodium carbonate solution was added to1,2-dimethoxyethane (10 mL) solution of 216 mg of2-bromo-5-nitrotoluene, 208 mg of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabororan-1-yl)-1H-pyrazole and10 mg of tetrakis(triphenylphosphine)palladium(0), and heated underreflux for 16 hours. The reaction liquid was washed with water, and theorganic layer was dried with anhydrous sodium sulfate. The solvent wasevaporated away under reduced pressure, and the crude product waspurified through silica gel column chromatography (hexane/ethyl acetate)to obtain 357 mg of the entitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.12 (1H, d, J=2.3 Hz), 8.04 (1H, dd, J=7.3,2.3 Hz), 7.70 (1H, s), 7.58 (1H, s), 8.12 (1H, d, J=7.3 Hz), 4.00 (3H,s), 2.51 (3H, s).

ESI-MS Found: m/z [M+H]+ 218.

2) Production of 3-methyl-4-(1-methyl-1H-pyrazol-4-yl)aniline

In the same manner as in Production Example 5-2, but using1-methyl-4-(2-methyl-4-nitrophenyl)-1H-pyrazole in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, 311 mg of the entitled compound was obtained as a whitesolid.

ESI-MS Found: m/z [M+H]+ 188.

PRODUCTION EXAMPLE 18 Production of3-methyl-4-{1-[2-(methylsulfonyl)ethyl]piperidin-4-yl}aniline 1)Production of 1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperidine

In the same manner as in Production Example 13-2 but using4-(4-nitrophenyl)piperidine in place of 1-(4-nitrophenyl)piperazinehydrochloride used in Production Example 13-2, the entitled compound wasobtained.

2) Production of3-methyl-4-{1-[2-(methylsulfonyl)ethyl]piperidin-4-yl}aniline

In the same manner as in Production Example 13-3 but using1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperidine in place of1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperazine used inProduction Example 13-3, 390 mg of the entitled compound was obtained asa white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.00 (2H, d; J=8.3 Hz), 6.64 (2H, d, J=8.3Hz), 3.58 (2H, s), 3.17 (2H, t, J=6.6 Hz), 3.07 (3H, s), 3.02 (2H, d,J=11.7 Hz), 2.89 (2H, t, J=6.6 Hz), 2.41 (1H, tt, J=12.0, 3.7 Hz), 2.15(2H, td, J=11.7, 2.4 Hz), 1.84 (2H, d, J=12.0 Hz), 1.66 (2H, ddd,J=25.4, 12.0, 3.7 Hz).

ESI-MS Found: m/z [M+H]+ 283.

PRODUCTION EXAMPLE 19 Production of2-methyl-N¹-(1-methylpiperidin-4-yl)benzene-1,4-diamine 1) Production of1-methyl-N-(2-methyl-4-nitrophenyl)piperidine-4-amine

In the same manner as in Production Example 5-1 but using1-methylpiperidine-4-amine in place of N-ethylpiperazine used inProduction Example 5-1, using 2-fluoro-5-nitrotoluene in place of2-fluoro-5-nitrobenzyl alcohol and using dimethylsulfoxide in place ofN-methylpyrrolidone, 1.2 g of the entitled compound was obtained as ayellow solid.

¹H-NMR (400 MHz, CD₃OD) δ: 7.99 (1H, dd, J=9.2, 2.7 Hz), 7.92 (1H, d,J=2.7 Hz), 6.68 (1H, d, J=9.2 Hz), 3.57-3.48 (1H, m), 2.97-2.89 (2H, m),2.33 (3H, s), 2.30-2.21 (2H, m), 2.19 (3H, s), 2.09-2.01 (2H, m),1.73-1.61 (2H, m).

2) Production of 2-methyl-N¹-(1-methylpiperidin-4-yl)benzene-1,4-diamine

In the same manner as in Production Example 13-3 but using1-methyl-N-(2-methyl-4-nitrophenyl)piperidine-4-amine in place of1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperazine used inProduction Example 13-3, 1.05 g of the entitled compound was obtained asa blue-violet solid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.38-6.29 (3H, m), 3.17 (1H, d, J=4.9 Hz),3.09-2.98 (1H, m), 2.83-2.73 (2H, m), 2.23 (3H, s), 2.16-2.04 (2H, m),1.99 (3H, s), 1.90-1.82 (2H, m), 1.47-1.35 (2H, m).

ESI-MS Found: m/z [M+H]+ 220.

PRODUCTION EXAMPLE 20 Production of3-methyl-4-[4-(methylsulfonyl)piperazin-1-yl]aniline 1) Production of1-(2-methyl-4-nitrophenyl)-4-(methylsulfonyl)piperazine

In the same manner as in Production Example 12-1 but usingmethanesulfonyl chloride in place of methoxyacetyl chloride used inProduction Example 12-1, 297 mg of the entitled compound was obtained asan orange solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.10-8.04 (2H, m), 7.04 (1H, d, J=8.3 Hz),3.46-3.40 (4H, 3.15-3.10 (4H, m), 2.87 (3H, s), 2.38 (3H, s).

ESI-MS Found: m/z [M+H]+ 300.

2) Production of 3-methyl-4-[4-(methylsulfonyl)piperazin-1-yl]aniline

In the same manner as in Production Example 13-3 but using1-(2-methyl-4-nitrophenyl)-4-(methylsulfonyl)piperazine in place of1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperazine used inProduction Example 13-3, 219 mg of the entitled compound was obtained asa pale brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.87 (1H, d, J=8.4 Hz), 6.57 (1H, d, J=2.8Hz), 6.53 (1H, dd, J=8.4, 2.8 Hz), 3.63 (2H, brs), 3.40-3.31 (4H, m),2.95-2.90 (4H, m), 2.84 (3H, s), 2.23 (3H, s).

ESI-MS Found: m/z [M+H]+ 270.

PRODUCTION EXAMPLE 21 Production of4-[(1-isopropylazetidin-3-yl)oxy]-3-methylaniline 1) Production of3-(2-methyl-4-nitrophenoxy)azetidine hydrochloride

Tert-butyl 3-(2-methyl-4-nitrophenoxy)azetidine-1-carboxylate wasobtained in the same manner as in Production Example 16-1, for which,however, 2-methyl-4-nitrophenol was used in place of2,6-dimethyl-4-nitrophenol used in Production Example 16-1, andtert-butyl 3-hydroxyazetidine-1-carboxylate was used in place of2-dimethylaminoethanol.

4 N hydrochloric acid/ethyl acetate solution was added to methanol (50mL) solution of the compound obtained in the above reaction, and stirredat room temperature for 30 minutes. The reaction liquid was concentratedunder reduced pressure to obtain 1.46 g of3-(2-methyl-4-nitrophenoxy)azetidine hydrochloride as a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 9.37 (2H, brs), 8.14 (1H, d, J=2.9 Hz),8.06 (1H, dd, J=9.0, 2.9 Hz), 6.93 (1H, d, J=9.0 Hz), 5.23 (1H, tt,J=6.6, 4.8 Hz), 4.47 (2H, dd, J=12.5, 6.6 Hz), 4.02 (2H, dd, J=12.5, 4.8Hz), 2.30 (3H, s).

ESI-MS Found: m/z [M+H]+ 209.

2) Production of 1-isopropyl-3-(2-methyl-4-nitrophenoxy)azetidine

In the same manner as in Production Example 11-1 but using3-(2-methyl-4-nitrophenoxy)azetidine hydrochloride in place of1-(2-methyl-4-nitrophenyl)piperazine hydrochloride used in ProductionExample 11-1, 142 mg of the entitled compound was obtained as a paleyellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.09-8.02 (2H, m), 6.63-6.58 (1H, m), 4.84(1H, quint, J=5.8 Hz), 3.91-3.84 (2H, m), 3.17-3.10 (2H, m), 2.43 (1H,sept, J=6.2 Hz), 2.29 (3H, s), 0.99 (6H, d, J=6.2 Hz).

ESI-MS Found: m/z [M+H]+ 251.

3) Production of 4-[(1-isopropylazetidin-3-yl)oxy]-3-methylaniline

In the same manner as in Production Example 13-3 but using1-(2-methyl-4-nitrophenyl)-4-(methylsulfonyl)piperazine in place of1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperazine used inProduction Example 13-3, 107 mg of the entitled compound was obtained asa pale brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.55-6.52 (1H, m), 6.47-6.40 (2H, m), 4.64(1H, quint, J=6.0 Hz), 3.85-3.78 (2H, m), 3.37 (2H, brs), 3.07-3.00 (2H,m), 2.40 (1H, sept, J=6.2 Hz), 2.15 (3H, s), 0.97 (6H, d, J=6.2 Hz).

ESI-MS Found: m/z [M+H]+ 221.

PRODUCTION EXAMPLE 22 Production of3-[4-(4-aminophenylpiperazin-1-yl)]propanenitrile 1) Production of3-[4-(4-nitrophenyl)piperazin-1-yl]propanenitrile

In the same manner as in Production Example 13-2 but using acrylonitrilein place of methylvinyl sulfone used in Production Example 13-2, 1.08 gof the entitled compound was obtained as a yellow solid.

2) Production of 3-[4-(4-aminophenylpiperazin-1-yl)]propanenitrile

In the same manner as in Production Example 5-2 but using3-[4-(4-nitrophenyl)piperazin-1-yl]propanenitrile in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, 159 mg of the entitled compound was obtained as a lightbrown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.83 (2H, d, J=8.4 Hz), 6.65 (2H, d, J=8.4Hz), 3.08 (4H, brs), 2.76 (2H, t, J=6.8 Hz), 2.69 (4H, brs), 2.56 (2H,t, J=6.8 Hz).

ESI-MS Found: m/z [M+H]+ 231.

PRODUCTION EXAMPLE 23 Production of1-[4-(4-aminophenyl)piperazin-1-yl]-3-fluoropropan-2-ol 1)Production of1-fluoro-3-[4-(4-nitrophenyl)piperazin-1-yl]propan-2-ol

Ethanol (15 mL) solution of 272 mg of epifluorohydrin and 500 mg of1-(4-nitrophenyl)piperazine was heated under reflux for 15 hours, andthen the reaction liquid was concentrated under reduced pressure. Theresidue was solidified from ethyl acetate to obtain 300 mg of theentitled compound as a yellow solid.

2) Production of 1-[4-(4-aminophenyl)piperazin-1-yl]-3-fluoropropan-2-ol

In the same manner as in Production Example 5-2 but using1-fluoro-3-[4-(4-nitrophenyl)piperazin-1-yl]propan-2-ol in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, 169 mg of the entitled compound was obtained as a brownliquid.

ESI-MS Found: m/z [M+H]+ 254.

PRODUCTION EXAMPLE 24 Production of1-[4-(4-aminophenyl)piperazin-1-yl]-2-methylpropan-2-ol 1) Production of2-methyl-1-[4-(4-nitrophenyl)piperazin-1-yl]propan-2-ol

In the same manner as in Production Example 23-1 but using1,2-epoxy-2-methylpropane in place of epifluorohydrin used in ProductionExample 23-1, 250 mg of the entitled compound was obtained as a yellowsolid.

2) Production of 1-[4-(4-aminophenyl)piperazin-1-yl]-2-methylpropan-2-ol

In the same manner as in Production Example 5-2 but using2-methyl-1-[4-(4-nitrophenyl)piperazin-1-yl]propan-2-ol in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, 180 mg of the entitled compound was obtained as a brownsolid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.81 (2H, d, J=8.4 Hz), 6.65 (2H, d, J=8.4Hz), 3.08 (4H, brs), 2.83 (4H, brs), 2.43 (2H, s), 1.21 (6H, s).

ESI-MS Found: m/z [M+H]+ 250.

PRODUCTION EXAMPLE 25 Production of2-[4-(4-aminophenyl)piperazin-1-yl]cyclopentanol 1) Production of2-[4-(4-nitrophenyl)piperazin-1-yl]cyclopentanol

In the same manner as in Production Example 23-1 but using cyclopenteneoxide in place of epifluorohydrin used in Production Example 23-1, 670mg of the entitled compound was obtained as a yellow solid.

2) Production of 2-[4-(4-aminophenyl)piperazin-1-yl]cyclopentanol

In the same manner as in Production Example 5-2 but using2-[4-(4-nitrophenyl)piperazin-1-yl]cyclopentanol in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, 159 mg of the entitled compound was obtained as a brownliquid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.81 (2H, d, J=8.4 Hz), 6.65 (2H, d, J=8.4Hz), 4.20-4.24 (1H, m), 3.11 (4H, brs), 2.81 (4H, brs), 2.58-2.64 (1H,m), 1.94-2.03 (2H, m), 1.59-1.74 (4H, m).

ESI-MS Found: m/z [M+H]+ 262.

PRODUCTION EXAMPLE 26 Production of4-(4-aminophenyl)-N,N-dimethylpiperazine-1-carboxamide 1) Production ofN,N-dimethyl-4-(4-nitrophenyl)piperazine-1-carboxamide

In the same manner as in Production Example 12-1 but usingdimethylcarbamoyl chloride in place of methoxyacetyl chloride used inProduction Example 12-1, 560 mg of he entitled compound was obtained asa yellow solid.

2) Production of 4-(4-aminophenyl)-N,N-dimethylpiperazine-1-carboxamide

In the same manner as in Production Example 13-3 but usingN,N-dimethyl-4-(4-nitrophenyl)piperazine-1-carboxamide in place of1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperazine used inProduction Example 13-3, 176 mg of the entitled compound was obtained asa brown solid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.86 (2H, d, J=8.4 Hz), 6.65 (2H, d, J=8.4Hz), 3.42 (4H, brs), 3.05 (4H, brs), 2.86 (6H, s).

ESI-MS Found: m/z [M+H]+ 249.

PRODUCTION EXAMPLE 27 Production of4-[4-(1-acetylazetidin-3-yl)piperazin-1-yl]aniline 1) Production of1-(1-acetylazetidin-3-yl)-4-(4-nitrophenyl)piperazine

0.581 mL of triethylamine and 0.185 mL of methanesulfonyl chloride wereadded to chloroform (15 mL) solution of 500 mg ofN-(diphenylmethyl)-3-hydroxyazetidine, and stirred at room temperaturefor 3 hours. Aqueous sodium carbonate solution was added to the reactionliquid, extracted with chloroform, dried with sodium sulfate, andevaporated under reduced pressure to obtain crudeN-(diphenylmethyl)-3-(methanesulfonyloxy)azetidine. 433 mg of1-(4-nitrophenyl)piperazine and 433 mg of potassium carbonate were addedto DMSO (10 mL) solution of the compound obtained in the above reaction,and heated at 100° C. for 3 hours. Water was added to the reactionliquid, extracted with ethyl acetate, and the organic layer was washedwith saturated saline water. The organic layer was dried with sodiumsulfate, concentrated under reduced pressure, and the crude product waspurified through column chromatography (ethyl acetate/hexane=2/1). Acatalytic amount of trifluoroborane ether solution was added to aceticanhydride (6 mL) solution of the obtained diphenylmethyl compound, andheated at 90° C. for 4 hours. The reaction liquid was concentrated underreduced pressure, sodium hydrogencarbonate was added to the residue, andextracted with chloroform. The organic layer was dried with sodiumsulfate, and then concentrated under reduced pressure. The crude productwas purified through column chromatography (methanol/chloroform=1/10),and then solidified from ethyl acetate/hexane to obtain 160 mg of theentitled compound as a yellow solid.

2) Production of 4-[4-(1-acetylazetidin-3-yl)piperazin-1-yl]aniline

In the same manner as in Production Example 5-2 but using1-(1-acetylazetidin-3-yl)-4-(4-nitrophenyl)piperazine in place of[5-nitro-2-(4-ethylpiperazin-1-yl)phenyl]methanol used in ProductionExample 5-2, 110 mg of the entitled compound was obtained as a brownsolid.

¹H-NMR (400 MHz, CDCl₃) δ: 6.82 (2H, d, J=8.4 Hz), 6.66 (2H, d, J=8.4Hz), 3.85-4.15 (4H, m), 3.18-3.25 (1H, m), 3.08 (41-1, brs), 2.54 (4H,brs), 1.87 (3H, s).

ESI-MS Found: m/z [M+H]+ 275.

PRODUCTION EXAMPLE 28 Production of2-[4-(4-aminophenyl)piperazin-1-yl]-N,N-dimethylacetamide 1) Productionof N,N-dimethyl-2-[4-(4-nitrophenyl)piperazin-1-yl]acetamide

In the same manner as in Production Example 27-1 but using2-chloro-N,N-dimethylacetamide in place ofN-(diphenylmethyl)-3-(methanesulfonyloxy)azetidine used in ProductionExample 27-1, 1.53 g of the entitled compound was used as a yellowsolid.

2) Production of2-[4-(4-aminophenyl)piperazin-1-yl]-N,N-dimethylacetamide

In the same manner as in Production Example 5-2 but usingN,N-dimethyl-2-[4-(4-nitrophenyl)piperazin-1-yl]acetamide in place of1-[2-(methylsulfonyl)ethyl]-4-(4-nitrophenyl)piperazine used inProduction Example 5-2, 1.2 g of the entitled compound was obtained as abrown solid.

¹H-NMR (CDCl₃) δ: 6.82 (2H, d, J=8.4 Hz), 6.65 (2H, d, J=8.4 Hz), 3.23(2H, s), 3.09 (4H, brs), 3.08 (3H, s), 2.96 (3H, s), 2.70 (4H, brs).

ESI-MS Found: m/z [M+H]+ 263.

EXAMPLE 1 Production of3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-[2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide

1) Production of methyl3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate

20 mL of pyridine was added to a chloroform solution of 7.5 g of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,6.1 g of copper(II) acetate and 10 g of[3-(methoxycarbonyl)]phenylboronic acid, and stirred at room temperaturefor 3 days. Aqueous 30% ammonia solution and saturated saline water wereadded to the reaction liquid in that order, and extracted withchloroform. The organic layer was washed with saturated saline water,then dried with anhydrous magnesium sulfate, and the solvent wasevaporated away. The crude product was purified through silica gelcolumn chromatography (hexane/ethyl acetate) to obtain 6.7 g of methyl3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoateas a yellow oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 8.92 (1H, s), 8.11-8.06 (2H, m), 7.65-7.59(2H, m), 5.68 (1H, ddd, J=17.1, 10.2, 5.9 Hz), 5.13 (1H, dd, J=10.2, 1.0Hz), 4.97 (1H, dd, J=17.1, 1.0 Hz), 4.45 (2H, d, J=5.9 Hz), 3.96 (3H,s), 2.51 (3H, s).

2) Production of methyl3-[2-allyl-6-(methylsulfinyl)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate

At 0° C., 6.5 g of m-chloroperbenzoic acid was added to a chloroformsolution of 6.7 g of the compound obtained in the above reaction, andstirred for 30 minutes. Aqueous saturated sodium hydrogencarbonatesolution was added to the reaction liquid, and extracted withchloroform/isopropanol (80/20). The organic layer was dried withanhydrous magnesium sulfate, and the solvent was evaporated away toobtain 5.6 g of crude methyl3-[2-allyl-6-(methylsulfinyl)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate.

3) Production of methyl3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate

0.87 g of 4-(4-methyl-1-piperazinyl)aniline and 2 mL ofN,N-diisopropylethylamine were added to a toluene solution of 1.7 g ofthe crude product obtained in the above reaction, and stirred at 70° C.for 12 hours. The solvent was evaporated away, and the product waspurified through silica gel column chromatography (chloroform/methanol)to obtain 2.2 g of methyl3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoateas a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 8.18-8.13 (1H, m), 8.04 (1H, d,J=7.8 Hz), 7.66-7.56 (2H, m), 7.45 (2H, d, J=8.5 Hz), 6.88 (2H, d, J=8.5Hz), 5.68 (1H, ddd, J=17.1, 10.2, 6.3 Hz), 5.10 (1H, dd, J=10.2, 1.0Hz), 4.98 (1H, dd, J=17.1, 1.0 Hz), 4.40 (2H, d, J=6.3 Hz), 3.97 (3H,s), 3.26-3.21 (4H, m), 2.72-2.64 (4H, m), 2.43 (3H, brs).

4) Production of3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide

Aqueous 1 N sodium hydroxide solution was added to a1,4-dioxane/methanol (50/50) solution of 2.2 g of methyl3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate,and stirred at room temperature for 2.5 hours. This was neutralized with1 N hydrochloric acid, and the solvent was evaporated away to obtain afree carboxylic acid of the starting ester. To an N,N-dimethylformamidesolution of the resulting carboxylic acid, added were 1.67 g of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1.18 g of1-hydroxybenzotriazole, and 11 mL of 1.0 M dimethylamine/tetrahydrofuransolution, and stirred at room temperature for 6 hours. Aqueous saturatedsodium hydrogencarbonate solution and water were added to the reactionliquid, extracted with chloroform/isopropanol (80/20), and purifiedthrough silica gel column chromatography (chloroform/methanol) to obtain560 mg of3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamideas a pale yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.57-7.51 (2H, m), 7.49-7.38(4H, m), 6.90 (2H, d, J=8.8 Hz), 5.69 (1H, ddt, J=17.1, 10.2, 6.3 Hz),5.10 (1H, dd, J=10.2, 1.0 Hz), 5.00 (1H, dd, J=17.1, 1.0 Hz), 4.40 (2H,d, J=6.3 Hz), 3.32 (3H, s), 3.14 (3H, s), 2.99-2.92 (4H, m), 2.84-2.71(4H, m), 2.50 (3H, s).

ESI-MS Found: m/z [M+H]+ 513.

EXAMPLE 2 Production of2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-phenyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

57 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-3, for which, however,2-phenyl-1,3,2-dioxaborynan was used in place of[3-(methoxycarbonyl)]phenylboric acid used in Example 1-1, and[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) 8.83 (1H, s), 7.15-7.62 (8H, m), 5.65-5.76 (1H,m), 5.10 (1H, d, J=10.3 Hz), 4.98 (1H, d, J=17.1 Hz), 4.74 (2H, s), 4.40(2H, d, J=5.8 Hz), 2.97-3.06 (4H, m), 2.51-2.77 (4H, m), 2.38 (3H, s).

ESI-MS Found: m/z [M+H]+ 472.

EXAMPLE 3 Production of2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

17.5 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-3, for which, however,3-thienylboronic acid was used in place of[3-(methoxycarbonyl)]phenylboric acid used in Example 1-1, and[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.17-7.63 (6H, m), 5.65-5.77(1H, m), 5.13 (1H, d, J=10.2 Hz), 5.04 (1H, d, J=17.1 Hz), 4.76 (2H, s),4.42 (2H, d, J=6.3 Hz), 2.98-3.06 (4H, m), 2.50-2.76 (4H, m), 2.39 (3H,s).

ESI-MS Found: m/z [M+H]+ 478.

EXAMPLE 4 Production of2-allyl-6-{[3-(hydroxymethyl)-4-morpholin-4-ylphenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

35.8 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-3, for which, however,3-thienylboronic acid was used in place of[3-(methoxycarbonyl)]phenylboric acid used in Example 1-1, and(5-amino-2-morpholin-4-ylphenyl)methanol was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.67-7.69 (1H, bs), 7.47-7.49(2H, m), 7.37 (1H, m), 7.15-7.23 (2H, m), 5.66-5.77 (1H, m), 5.14 (1H,d, J=10.3 Hz), 5.04 (1H, d, J=18.5 Hz), 4.77 (2H, s), 4.42 (2H, d, 5.8Hz), 3.83-3.89 (4H, m), 2.95-2.99 (4H, m).

ESI-MS Found: m/z [M+H]+ 465.

EXAMPLE 5 Production of2-allyl-1-[3-(hydroxymethyl)phenyl]-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

5.0 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-3, for which, however,[3-(hydroxyethyl)phenyl]boronic acid was used in place of[3-(methoxycarbonyl)]phenylboric acid used in Example 1-1, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.53-7.45 (2H, m), 7.41-7.32(4H, m), 6.99 (1H, d, J=8.3 Hz), 5.69 (1H, ddt, J=17.1, 10.2, 6.3 Hz),5.10 (1H, dd, J=10.2, 1.0 Hz), 4.99 (1H, dd, J=17.1, 1.5 Hz), 4.79 (2H,s), 4.39 (2H, d, J=6.3 Hz), 2.96-2.91 (4H, m), 2.68-2.58 (4H; m), 2.40(3H, s), 2.26 (3H, s).

ESI-MS Found: m/z [M+H]+ 486.

EXAMPLE 6 Production of2-allyl-{[4-(hydroxymethyl)phenyl]-6-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

5.6 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-3, for which, however,[4-(hydroxymethyl)phenyl]boronic acid was used in place of[3-(methoxycarbonyl)]phenylboric acid used in Example 1-1, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.52 (2H, d, J=8.8 Hz),7.50-7.39 (1H, m), 7.44 (2H, d, J=8.8 Hz), 7.26-7.22 (1H, m), 6.97 (1H,d, J=8.3 Hz), 5.69 (1H, ddt, J=17.1, 10.2, 6.3 Hz), 5.10 (1H, dd,J=10.2, 1.0 Hz), 4.98 (1H, dd, J=17.1, 1.0 Hz), 4.78 (2H, s), 4.38 (2H,d, J=6.3 Hz), 2.97-2.89 (4H, m), 2.70-2.55 (4H, m), 2.40 (3H, s), 2.28(3H, s).

ESI-MS Found: m/z [M+H]+ 486.

EXAMPLE 7 Production of3-(2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile

62 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-3, for which, however,3-cyanophenylboronic acid was used in place of[3-(methoxycarbonyl)]phenylboric acid used in Example 1-1, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.86 (1H, s), 7.69-7.59 (3H,m), 7.36-7.32 (2H, m), 7.06 (1H, d, J=8.8 Hz), 5.68 (1H, ddt, J=17.1,10.2, 5.9 Hz), 5.13 (1H, dd, J=10.2, 1.0 Hz), 5.00 (1H, dd, J=17.1, 1.0Hz), 4.38 (2H, d, J=5.9 Hz), 2.98-2.91 (4H, m), 2.66-2.52 (4H, m), 2.38(3H, s), 2.31 (3H, s).

ESI-MS Found: m/z [M+H]+ 481.

EXAMPLE 8 Production of2-allyl-1-(3-methoxyphenyl)-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

52 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-3, for which, however,3-methoxyphenylboronic acid was used in place of[3-(methoxycarbonyl)]phenylboric acid used in Example 1-1, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.50-7.40 (1H, m), 7.41 (1H, t,J=8.0 Hz), 7.30 (1H, dd, J=8.0, 2.7 Hz), 7.05-6.90 (4H, m), 5.71 (1H,ddt, J=17.1, 10.2, 5.9 Hz), 5.11 (1H, dd, J=10.2, 1.0 Hz), 5.01 (1H, dd,J=17.1, 1.0 Hz), 4.40 (2H, d, J=5.9 Hz), 3.83 (3H, s), 2.94-2.89 (4H,m), 2.64-2.54 (4H, m), 2.37 (3H, s), 2.27 (3H, s).

ESI-MS Found: m/z [M+H]+ 486.

EXAMPLE 9 Production of3-(2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide

30 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-4, for which, however,3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.58-7.52 (3H, m), 7.49-7.47(1H, m), 7.44-7.40 (1H, m), 7.38-7.32 (2H, m), 6.98 (1H, d, J=8.8 Hz),5.69 (1H, ddt, J=17.1, 10.2, 5.9 Hz), 5.10 (1H, dd, J=10.2, 1.0 Hz),5.00 (1H, dd, J=17.1, 1.0 Hz), 4.39 (2H, d, J=5.9 Hz), 3.13 (3H, s),2.97 (3H, s), 2.95-2.91 (4H, m), 2.67-2.55 (4H, m), 2.38 (3H, s), 2.28(3H, s).

ESI-MS Found: m/z [M+H]+ 527.

EXAMPLE 10 Production of3-[2-allyl-6-({4-[4-(2-hydroxyethyl)piperazin-1-yl]-3-methylphenyl}amino)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]-N,N-dimethylbenzamide

13.6 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-4, for which, however,3-methyl-4-[(4-hydroxyethyl)piperazin-1-yl]aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.59-7.53 (2H, m), 7.48 (1H, d,J=1.0 Hz), 7.44-7.41 (1H, m), 7.38-7.33 (2H, m), 6.98 (1H, d, J=8.3 Hz),5.69 (1H, ddt, J=17.1, 10.2, 6.3 Hz), 5.11 (1H, dd, J=10.2, 1.5 Hz),5.00 (1H, dd, J=17.1, 1.5 Hz), 4.40 (2H, d, J=6.3 Hz), 3.68 (2H, t,J=5.4 Hz), 3.14 (3H, s), 2.98 (3H, s), 2.96-2.91 (4H, m), 2.76-2.67 (4H,m), 2.65 (2H, t, J=5.4 Hz), 2.28 (3H, s).

ESI-MS Found: m/z [M+H]+ 557.

EXAMPLE 11 Production of3-(2-allyl-6-{[4-(4-cyclopropylpiperazin-1-yl)phenyl)amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]-N,N-dimethylbenzamide

32.3 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-4, for which, however,4-(4-cyclopropylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.41-7.54 (5H, m), 6.88 (1H, d,J=8.3 Hz), 5.63-5.74 (1H, m), 5.09 (1H, d, J=10.0 Hz), 4.99 (1H, d,J=17.2 Hz), 4.39 (2H, d, J=5.8 Hz), 3.10-3.21 (6H, m), 2.75-2.99 (8H,m), 1.67-1.82 (1H, m), 0.45-0.55 (4H, m).

ESI-MS Found: m/z [M+H]+ 539.

EXAMPLE 12 Production of3-(2-allyl-6-{[4-(4-cyclopropylpiperazin-1-yl)-3-methylphenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide

49.6 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-4, for which, however,3-methyl-4-(4-cyclopropylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.26-7.56 (6H, m), 6.95 (1H, d,J=8.5 Hz), 5.63-5.73 (1H, m), 5.10 (1H, d, J=10.1 Hz), 4.98 (1H, d,J=16.9 Hz), 4.39 (2H, d, J=5.9 Hz), 3.13 (3H, s), 2.97 (3H, s), 2.89(4H, s), 2.79 (4H, s), 2.29 (3H, s), 1.67-1.85 (1H, m), 0.47-0.54 (4H,m).

ESI-MS Found: m/z [M+H]+ 553.

EXAMPLE 13 Production of3-(2-allyl-6-{[4-(4-cyclopropylpiperazin-1-yl)-3-(hydroxymethyl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide

24.3 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-4, for which, however,[5-amino-2-(4-cyclopropylpiperazin-1-yl)phenyl]methanol was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.27-7.65 (6H, m), 7.12 (1H, d,J=8.0 Hz), 6.63-6.72 (1H, m), 5.10 (1H, d, J=10.0 Hz), 4.97 (1H, d,J=17.1 Hz), 4.74 (2H, s), 4.39 (2H, d, J=5.8 Hz), 3.14 (3H, s), 2.99(3H, s), 2.95 (4H, s), 2.75-2.92 (4H, m), 2.69-2.75 (1H, m), 0.45-0.56(4H, m).

ESI-MS Found: m/z [M+H]+ 569.

EXAMPLE 14 Production of3-(2-allyl-6-{[4-(1,1-dioxido-thiomorpholin-4-yl)-3-methylphenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide

10.8 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-4, for which, however,3-methyl-4-(1,1-dioxido-thiomorpholin-4-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.39-7.61 (6H, m), 7.04 (1H, d,J=8.0 Hz), 5.65-5.77 (1H, m), 5.11 (1H, d, J=10.1 Hz), 5.99 (1H, d,J=17.3 Hz), 4.40 (2H, d, J=5.9 Hz), 3.37-3.42 (4H, m), 3.18-3.21 (4H,m), 3.15 (3H, s), 3.01 (3H, s), 2.28 (3H, s).

ESI-MS Found: m/z [M+H]+ 562.

EXAMPLE 15 Production of3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-diethylbenzamide

58.5 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-4, for which, however,N,N-diethylamine was used in place of N,N-dimethylamine used in Example1-4.

¹HNMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.56-7.43 (5H, m), 7.37 (1H, d,J=7.3 Hz), 6.91 (2H, d, J=8.8 Hz), 5.69 (1H, ddt, J=17.1, 10.2, 5.9 Hz),5.10 (1H, dd, J=10.2, 1.0 Hz), 4.99 (1H, dd, J=17.1, 1.0 Hz), 4.39 (2H,d, J=5.9 Hz), 3.57 (2H, brs), 3.25 (4H, brs), 2.67 (4H, s), 2.42 (3H,s), 1.26 (3H, brs), 1.10 (3H, brs).

ESI-MS Found: m/z [M+H]+ 541.

EXAMPLE 16 Production of3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-ethyl-N-methylbenzamide

65.2 mg of the entitled compound was obtained as a yellow amorphoussubstance in the same manner as in Example 1-1 to 1-4, for which,however, N-ethyl-N-methylamine was used in place of N,N-dimethylamineused in Example 1-4.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.57-7.35 (6H, m), 6.90 (2H, d,J=8.3 Hz), 5.69 (1H, ddt, J=17.1, 10.0, 6.3 Hz), 5.10 (1H, dd, J=10.0,1.2 Hz), 5.00 (1H, dd, J=17.1, 1.5 Hz), 4.40 (2H, d, J=6.3 Hz), 3.60(1H, brs), 3.22 (5H, s), 3.09 (2H, s), 2.91 (1H, s), 2.64 (4H, s), 2.39(3H, s), 1.25 (3H, brs), 1.10 (3H, brs).

ESI-MS Found: m/z [M+H]+ 527.

EXAMPLE 17 Production of3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N-(2-hydroxyethyl)-N-methylbenzamide

76.1 mg of the entitled compound was obtained as a yellow amorphoussubstance in the same manner as in Example 1-1 to 1-4, for which,however, N-(2-hydroxyethyl)-N-methylamine was used in place ofN,N-dimethylamine used in Example 1-4.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.67-7.37 (6H, m), 6.91 (2H, d,J=7.3 Hz), 5.68 (1H, ddt, J=17.1, 10.2, 6.3 Hz), 5.10 (1H, dd, J=10.2,1.0 Hz), 4.99 (1H, d, J=17.1 Hz), 4.39 (2H, d, J=6.3 Hz), 3.91 (1H, s),3.73 (1H, s), 3.41 (1H, s), 3.23-3.11 (6H, brm), 3.00 (2H, brs), 2.61(4H, s), 2.37 (3H, s).

ESI-MS Found: m/z [M+H]+ 543.

EXAMPLE 18 Production of2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-nitrophenyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

32 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-3, for which, however,3-nitrophenylboronic acid was used in place of[3-(methoxycarbonyl)]phenylboronic acid used in Example 1-1 and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 8.41 (1H, s), 8.22-8.18 (1H,m), 7.81-7.77 (1H, m), 7.68 (1H, t, J=8.0 Hz), 7.41-7.36 (1H, m), 7.30(1H, d, J=2.4 Hz), 7.02 (1H, d, J=8.0 Hz), 5.70 (1H, ddt, J=17.2, 10.2,6.3 Hz), 5.13 (1H, dd, J=10.2, 1.0 Hz), 5.01 (1H, dd, J=17.2, 1.0 Hz),4.41 (3H, d, J=6.3 Hz), 2.97-2.92 (4H, m), 2.67-2.54 (4H, m), 2.39 (3H,s), 2.27 (3H, s).

ESI-MS Found: m/z [M+H]+ 501.

EXAMPLE 19 Production of2-allyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of 3-(1-hydroxy-1-methylethyl)phenylboronic acid

In a nitrogen atmosphere with cooling with ice, 5.29 mL of3′-bromoacetophenone was added to 25 mL of 2 M methylmagnesiumiodide/diethyl ether solution and 100 mL of diethyl ether, and stirredfor 20 minutes. Water and 2 N hydrochloric acid were added to thereaction liquid, extracted with ethyl acetate, washed with aqueoussaturated sodium hydrogencarbonate solution and saturated saline water,and dried with anhydrous magnesium sulfate. The solvent was evaporatedaway under reduced pressure to obtain crude2-(3-bromophenyl)propan-2-ol.

In a nitrogen atmosphere, 33 mL of 1.66 M n-butyllithium/hexane solutionwas dropwise added to tetrahydrofuran (200 mL) solution of the obtainedcompound at −60° C. or lower, and stirred for 20 minutes. 11.08 mL oftriisopropoxyborane was added to the reaction liquid, and stirred for 30minutes. Water was added to the reaction liquid, washed with diethylether, and the resulting aqueous layer was made acidic with aqueous 10%phosphoric acid solution. This was extracted with ethyl acetate, washedwith aqueous saturated sodium hydrogencarbonate solution and saturatedsaline water, and dried with anhydrous magnesium sulfate. The solventwas evaporated away under reduced pressure, and the resulting crystalwas collected to obtain 3.13 g of the entitled compound as a whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.96 (2H, s), 7.88 (1H, brs), 7.60 (1H, d,J=7.3 Hz), 7.50 (1H, d, J=8.3 Hz), 7.24 (1H, t, J=7.6 Hz), 4.93 (1H, s),1.43 (6H, d, J=13.7 Hz).

2) Production of2-allyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

35.2 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-3, for which, however, the aboveboronic acid was used in place of [3-(methoxycarbonyl)]phenylboronicacid used in Example 1-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.57 (1H, s), 7.47 (2H, d,J=4.9 Hz), 7.43 (2H, d, J=8.8 Hz), 7.31-7.28 (1H, m), 6.88 (2H, d, J=8.8Hz), 5.70 (1H, ddt, J=17.1, 10.0, 6.3 Hz), 5.10 (1H, dd, J=10.0, 1.2Hz), 4.98 (1H, dd, J=17.1, 1.5 Hz), 4.38 (2H, d, J=6.3 Hz), 3.21 (4H, t,J=4.1 Hz), 2.66 (4H, s), 2.41 (3H, s), 1.62 (6H, s).

ESI-MS Found: m/z [M+H]+ 500.

EXAMPLE 20 Production of2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-4-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

5.4 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 1-1 to 1-3, for which, however,pyridin-4-ylboronic acid was used in place of[3-(methoxycarbonyl)]phenylboronic acid used in Example 1-1, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 8.72 (2H, dd, J=4.9, 1.5 Hz),7.48 (2H, d, J=5.9 Hz), 7.03 (1H, d, J=8.8 Hz), 5.67 (1H, ddt, J=17.1,10.2, 6.3 Hz), 5.12 (1H, dd, J=10.2, 1.2 Hz), 5.03 (1H, dd, J=17.1, 1.2Hz), 4.44 (2H, d, J=6.3 Hz), 2.97 (4H, t, J=4.4 Hz), 2.64 (4H, s), 2.41(3H, s), 2.34 (3H, s).

ESI-MS Found: m/z [M+H]+ 457.

EXAMPLE 21 Production of2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-3-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

26.5 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 1-1 to 1-3, for which, however,pyridin-3-ylboronic acid was used in place of[3-(methoxycarbonyl)]phenylboronic acid used in Example 1-1, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 8.80 (1H, d, J=2.4 Hz), 8.63(1H, dd, J=4.4, 1.5 Hz), 7.79 (1H, d, J=7.8 Hz), 7.46 (2H, dd, J=8.0,4.6 Hz), 6.99 (1H, d, J=8.8 Hz), 5.69 (1H, ddt, J=17.1, 10.2, 6.3 Hz),5.12 (1H, dd, J=10.2, 1.0 Hz), 4.99 (1H, dd, J=17.1, 1.0 Hz), 4.40 (2H,d, J=6.3 Hz), 2.93 (4H, t, J=4.6 Hz), 2.61 (4H, s), 2.39 (3H, s), 2.30(3H, s).

ESI-MS Found: m/z [M+H]+ 457.

EXAMPLE 22 Production of2-allyl-1-[3-(2-hydroxy-2-methylpropyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of 1-(3-bromophenyl)-2-methylpropan-1-ol

With cooling with ice, 150 mL of 1.0 M isopropylmagnesiumchloride/tetrahydrofuran solution was added to tetrahydrofuran (200 mL)solution of 21.9 g of 3-bromobenzaldehyde. 4 N hydrochloric acid wasadded to the reaction liquid, extracted with diethyl ether, and washedwith saturated sodium hydrogencarbonate solution and saturated salinewater in that order. This was dried with anhydrous magnesium sulfate,the solvent was evaporated away under reduced pressure, and theresulting residue was purified through silica gel column chromatography(hexane/ethyl acetate=19/1 to 4/1) to obtain 4.20 g of the entitledcompound as an oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.48 (1H, s), 7.40 (1H, td, J=2.0, 7.3 Hz),7.25-7.18 (2H, m), 4.36 (1H, d, J=6.8 Hz), 1.94 (1H, qq, J=6.8, 6.8 Hz),0.98 (3H, d, J=6.8 Hz), 0.83 (3H, d, J=6.8 Hz).

2) Production of 1-bromo-3-(2-methyl-1-propylene-1-yl)benzene

2.4 g of p-toluenesulfonic acid monohydrate was added to toluene (70 mL)solution of 4 g of the alcohol obtained in the above 1, and heated underreflux for 2 hours. With cooling with ice, saturated sodiumhydrogencarbonate solution was added to it and diluted with ethylacetate. The organic layer was washed with saturated sodiumhydrogencarbonate solution and saturated saline water in that order, anddried with anhydrous sodium sulfate. The solvent was evaporated awayunder reduced pressure, and the resulting residue was separated andpurified through silica gel column chromatography (hexane) to obtain 1.9g of the entitled compound as an oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.38-7.35 (1H, m), 7.32-7.29 (1H, m),7.21-7.11 (2H, m), 6.19 (1H, s), 1.90 (3H, d, J=1.5 Hz), 1.85 (3H, d,J=1.5 Hz).

3) Production of 3-(3-bromophenyl)-2,2-dimethyloxirane

With cooling with ice, 3.4 g of m-chloroperbenzoic acid was graduallyadded to chloroform (40 mL) solution of 1.9 g of the alkene obtained inthe above 2, and stirred at room temperature for 2 hours. Sodium sulfitesolution was added to the reaction solution, and stirred at roomtemperature for 1 hour. Water was added to it, and washed with 0.1 Nsodium hydroxide solution, saturated sodium hydrogencarbonate solutionand saturated saline water in that order, and dried with anhydroussodium sulfate. The solvent was evaporated away under reduced pressureto obtain 2.0 g of the entitled compound as an oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.46-7.44 (1H, m), 7.43-7.38 (1H, m),7.24-7.20 (2H, m), 3.82 (1H, s), 1.48 (3H, s), 1.08 (3H, s).

4) Production of 1-(3-bromophenyl)-2-methyl-2-propanol

In a nitrogen atmosphere at −78° C., 16 mL of 1.0 M diisobutylaluminiumhydride/toluene solution was dropwise added to dichloromethane (100 mL)solution of 1.8 g of the oxirane obtained in the above 3, and stirredfor 20 minutes. 20 mL of aqueous 30% Rochelle salt solution was added tothe reaction solution, stirred at 0° C. for 2 hours, and then theinsoluble matter was removed through filtration through Celite. Thefiltrate was washed with aqueous 30% Rochelle salt solution, saturatedsodium hydrogencarbonate solution and saturate saline water in thatorder, and dried with anhydrous sodium sulfate. The solvent wasevaporated away under reduced pressure, and the resulting residue wasseparated and purified through silica gel column chromatography(hexane/ethyl acetate=4/1) to obtain 870 mg of the entitled compound asan oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.41-7.36 (2H, m), 7.21-7.12 (2H, m), 2.73(2H, s), 1.23 (6H, s).

5) Production of [3-(2-hydroxy-2-methylpropyl)phenyl]boronic acid

In a nitrogen atmosphere at −78° C., 5.5 mL of 1.58 Mn-butyllithium/hexane solution was dropwise added to tetrahydrofuran (50mL) solution of 870 mg of the alcohol, obtained in the above 4, then 925mg of triisopropylboronic acid was dropwise added thereto, and stirredfor 20 minutes. Water was added to the reaction solution, and washedwith diethyl ether. The aqueous layer was made weakly acidic with 10%phosphoric acid, and then extracted with ethyl acetate. The organiclayer was washed with water and saturated saline water in that order,and dried with anhydrous sodium sulfate. The solvent was evaporated awayunder reduced pressure to obtain 274 mg of the entitled compound. Notpurified, this was used in the next reaction.

6) Production of2-allyl-1-[3-(2-hydroxy-2-methylpropyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

In the same manner as in Example 1-1 to 1-3, 48 mg of the entitledcompound was obtained as a yellow solid, for which, however, the boronicacid obtained in the above 5 was used in place of[3-(methoxycarbonyl)]phenylboronic acid used in Example 1-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.55-7.20 (7H, m), 6.88 (2H, d,J=9.0 Hz), 5.70 (1H, ddt, J=17.2, 10.2, 5.9 Hz), 5.10 (1H, d, J=10.2Hz), 4.98 (1H, d, J=17.2 Hz), 4.39 (2H, d, J=5.9 Hz), 3.28-3.18 (4H, m),2.84 (2H, s), 2.75-2.60 (4H, m), 2.43 (3H, s), 1.25 (6H, s).

ESI-MS Found: m/z [M+H]+: 514.

EXAMPLE 23

Production ofN-[3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl]acetamide

42 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-3, for which, however,[3-(acetylamino)phenyl]boronic acid was used in place of[3-(methoxycarbonyl)]phenylboronic acid used in Example 1-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.78 (1H, s), 7.65-7.55 (3H, m), 7.49-7.37(4H, m), 7.22-7.14 (1H, m), 6.90-6.81 (2H, m), 5.68 (1H, ddt, J=17.1,10.2, 5.4 Hz), 5.09 (1H, d, J=10.2 Hz), 5.00 (1H, d, J=17.1 Hz), 4.41(2H, d, J=5.4 Hz), 3.25-3.13 (4H, m), 2.69-2.55 (4H, m), 2.38 (3H, s),2.22 (3H, s).

ESI-MS Found: m/z [M+H]+ 499.

EXAMPLE 24 Production of2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1-[3-(methylsulfonyl)phenyl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

75 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-3, for which, however,[3-(methylsulfonyl)phenyl]boronic acid was used in place of[3-(methoxycarbonyl)]phenylboronic acid used in Example 1-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 8.17 (1H, s), 7.93-7.81 (1H,m), 7.76-7.60 (2H, m), 7.60-7.48 (1H, m), 7.44 (2H, d, J=8.3 Hz), 6.97(2H, d, J=8.3 Hz), 5.69 (1H, ddt, J=17.1; 10.2, 5.9 Hz), 5.13 (1H, d,J=10.2 Hz), 5.01 (1H, d, J=17.1 Hz), 4.40 (2H, d, J=5.9 Hz), 3.30-3.19(4H, m), 2.98 (3H, s), 2.74-2.59 (4H, m), 2.41 (3H, s).

ESI-MS Found: m/z [M+H]+ 520.

EXAMPLE 25 Production of2-allyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-6-{[4-(1-methylpiperazin-4-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

26.3 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 1-1 to 1-3, for which, however, the boronicacid obtained in Example 19-1 was used in place of[3-(methoxycarbonyl)]phenylboronic acid used in Example 1-1, and4-(1-methylpiperidin-4-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.61 (1H, s), 7.52-7.46 (4H,m), 7.42 (1H, brs), 7.31-7.28 (1H, m), 7.17 (2H, d, J=8.3 Hz), 5.71 (1H,ddt, J=17.1, 10.2, 5.9 Hz), 5.11 (1H, d, J=10.2 Hz), 4.98 (1H, d, J=17.1Hz), 4.39 (2H, d, J=5.9 Hz), 3.03 (2H, d, J=10.7 Hz), 2.51-2.41 (1H, m),2.37 (3H, s), 2.18-2.07 (2H, m), 1.99-1.78 (4H, m), 1.63 (6H, s).

ESI-MS Found: m/z [M+H]+ 499.

EXAMPLE 26 Production of2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

2.9 mL of methanesulfonyl chloride and 11 mL ofN,N-diisopropylethylamine were added in that order to chloroform (50 mL)solution of 3.0 g of2-allyl-1-[3-(hydroxymethyl)phenyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onethat had been obtained by the use of [3-(hydroxymethyl)phenyl]boronicacid in place of [3-(methoxycarbonyl)]phenylboronic acid used in Example1-1, and stirred at room temperature for 1 hour. The reaction liquid waswashed with 0.5 N hydrochloric acid, and dried with anhydrous sodiumsulfate. The solvent was evaporated away under reduced pressure toobtain crude2-allyl-1-[3-(methylsulfonyloxymethyl)phenyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneas a yellow oily substance.

20 mL of 2 M dimethylamine/tetrahydrofuran solution was added totetrahydrofuran (100 mL) solution of 1.5 g of the above compound, andstirred at room temperature for 18 hours. The solvent was evaporatedaway under reduced pressure, and the residue was separated and purifiedthrough silica gel column chromatography (ethyl acetate) to obtain 2.5 gof the entitled compound as a yellow Solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.90 (1H, s), 7.53-7.26 (4H, m), 5.73-5.62(1H, m), 5.11 (1H, dd, J=10.2, 1.0 Hz); 4.95 (1H, dd, J=17.1, 1.0 Hz),4.44 (211, d, J=3.7 Hz), 3.49 (2H, s), 2.48 (3H, s), 2.27 (6H, s).

ESI-MS Found: m/z M+H]+ 356.1.

2) Production of2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

4 N hydrochloric acid/ethyl acetate solution was added to 100 mg of thecompound obtained in the above 1, stirred at room temperature, and thesolvent was evaporated away under reduced pressure to obtain2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onehydrochloride.

70 mg of m-chloroperbenzoic acid was added to N,N-dimethylformamide (2mL) solution of the above compound, and stirred at room temperature for15 minutes. The reaction liquid was washed with aqueous saturated sodiumhydrogencarbonate solution, and dried with anhydrous sodium sulfate. Thesolvent was evaporated away under reduced pressure to obtain crude2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-(methylsulfinyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneas a white solid.

50 mg of 4-(4-methylpiperazin-1-yl)aniline and 0.1 mL ofN,N-diisopropylethylamine were added in that order todimethylsulfoxide/toluene (1/10, 10 mL) solution of the above compound,and stirred at 120° C. for 15 hours. The solvent was evaporated awayunder reduced pressure, water was added thereto, and extracted withethyl acetate and dried with anhydrous sodium sulfate. The solvent wasevaporated away under reduced pressure, and the residue was separatedand purified through basic silica gel column chromatography (entylacetate) to obtain 11.4 mg f the entitled compound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.48-7.33 (6H, m), 6.87 (2H, d,J=8.8 Hz), 5.80-5.60 (1H, m), 5.09 (1H, dd, J=10.2, 1.0 Hz), 4.97 (1H,dd, J=17.1, 1.5 Hz), 4.38 (1H, d, J=5.9 Hz), 3.51 (2H, s), 3.18 (4H, t,J=4.9 Hz), 2.60 (4H, t, J=4.9 Hz), 2.37 (3H, s), 2.28 (6H, s).

ESI-MS Found: m/z [M+H]+ 499.

EXAMPLE 27 Production of2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-[3-(pyrrolidin-1-ylmethyl)phenyl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

12 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 26-1 to 26-2, for which, however, pyrrolidinewas used in place of N,N-dimethylamine used in Example 26-1, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 26-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.28-7.48 (6H, m), 6.95 (1H, d,J=8.5 Hz), 5.62-5.78 (1H, m), 5.09 (1H, d, J=10.3 Hz), 4.93 (1H, d,J=17.5 Hz), 4.37 (2H, d, J=6.1 Hz), 3.69 (2H, s), 2.90 (4H, t, J=4.7Hz), 2.50-2.62 (8H, m), 2.36 (3H, s), 2.26 (3H, s), 1.72-1.90 (4H, m).

ESI-MS Found: m/z [M+H]+ 539.

EXAMPLE 28 Production of3-(2-ethyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide 1)Production of2-ethyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

5.8 g of the entitled compound was obtained as a yellow solid in thesame manner as in Production example 1-2, for which, however, tert-butyl1-ethylhydrazinecarboxylate was used in place of tert-butyl1-allylhydrazinecarboxylate used in Production Example 1-2.

¹H-NMR (400 MHz, CDCl₃) δ: 9.10 (1H, s), 4.18 (2H, q, J=7.1 Hz), 2.67(3H, s), 1.48 (3H, t, J=7.1 Hz).

ESI-MS Found: m/z [M+H]+ 211.

2) Production of3-(2-ethyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide

24.8 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-1 to 1-4, for which, however,2-ethyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in the above was used in place of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 1-1, and 3-methyl-4-(4-methylpiperazin-1-yl) aniline wasused in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.60-7.48 (4H, m), 7.44-7.32(3H, m), 6.98 (1H, d, J=8.3 Hz), 3.87 (2H, q, J=7.0 Hz), 3.14 (3H, s),2.98 (3H, s), 2.95-2.91 (4H, m), 2.67-2.54 (4H, m), 2.38 (3H, s), 2.29(3H, s), 1.07 (3H, t, J=7.0 Hz).

ESI-MS Found: m/z [M+H]+ 515.

EXAMPLE 29 Production of2-allyl-6-{[3-hydroxymethyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

1) Production of2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one

2.4 mL of N,N′-dimethylethylenediamine was added to 1,4-dioxane (50 mL)solution of 4.44 g of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,3.80 g of copper(I) iodide, 5.33 g of 2-iodopyridine and 3.80 g ofpotassium carbonate, and stirred overnight at 95° C. The reaction liquidwas cooled, aqueous ammonia was added thereto and extracted with ethylacetate, washed with saturated saline water and dried with anhydrousmagnesium sulfate. The solvent was evaporated away under reducedpressure, and crystallized with ethyl acetate to obtain 5.15 g of theentitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.94 (1H, s), 8.52 (1H, d, J=5.1 Hz), 7.90(2H, d, J=3.5 Hz), 7.29-7.25 (1H, m), 5.68 (1H, ddt, J=17.0, 10.2, 6.3Hz), 5.05 (1H, d, J=10.2 Hz), 4.91 (1H, d, J=17.0 Hz), 4.85 (1H, d,J=6.3 Hz), 2.58 (3H, s).

ESI-MS Found: m/z [M+H]+ 300.

2) Production of2-allyl-6-{[3-hydroxymethyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

796 mg of m-chloroperbenzoic acid (>65%) was added to toluene (20 mL)solution of 898 mg of2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one,and stirred for 30 minutes. 1.60 mL of N,N-diisopropylethylamine, 800 mgof [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol and 10 mL oftetrahydrofuran were added to the reaction liquid, and stirredovernight. Aqueous saturated sodium hydrogencarbonate solution was addedto the reaction liquid, and extracted with a mixed solution ofchloroform/isopropanol (80/20). This was dried with anhydrous magnesiumsulfate, the solvent was evaporated away, and the residue was purifiedthrough basic silica gel column chromatography (hexane/ethylacetate=50/50 to 0/100). The resulting crystal was recrystallized fromethanol to obtain 941 mg of the entitled compound as a white crystal.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 8.53 (1H, d, J=4.8 Hz), 7.91(1H, dd, 7.88 (1H, dd, J=8.8, 7.6 Hz), 7.87 (1H, d, J=7.6 Hz), 7.64 (1H,s), 7.33 (1H, d, J=8.8 Hz), 7.26 (1H, dd, J=8.8, 4.8 Hz), 7.19 (1H, d,J=8.8 Hz), 5.68 (1H, ddd, J=17.2, 10.4, 5.6 Hz), 5.50 (1H, s), 5.01 (1H,d, 10.4 Hz), 4.91 (1H, d, J=17.2 Hz), 4.79 (2H, s), 4.79 (2H, d, J=5.6Hz), 3.01 (4H, m), 2.62 (4H, m), 2.37 (3H, s).

ESI-MS Found: m/z [M+H]+ 472.

EXAMPLE 30 Production of2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

18.8 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.88 (1H, dd, J=8.0, 8.0 Hz),7.86 (1H, d, J=8.0 Hz), 7.52 (1H, s), 7.26 (1H, d, J=8.0, 4.8 Hz), 7.25(1H, J=8.4 Hz), 7.01 (1H, d, J=4.8 Hz), 5.68 (1H, ddd, J=17.2, 10.0, 6.0Hz), 5.01 (1H, d, J=10.0 Hz), 4.91 (1H, J=17.2 Hz), 4.79 (1H, J=6.0 Hz),2.94 (4H, m), 2.61 (4H, m), 2.37 (3H, s), 2.32 (3H, s).

ESI-MS Found: m/z [M+H]+ 457.

EXAMPLE 31 Production of2-allyl-6-({4-[4-(2-hydroxyethyl)piperazin-1-yl]-3-methylphenyl}amino)=1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

95 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,4-[4-(hydroxyethyl)piperazin-1-yl]aniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 8.49 (1H, dd, J=5.0, 1.1 Hz),7.88-7.80 (2H, m), 7.51-7.45 (1H, m), 7.29 (1H, dd, J=8.5, 2.6 Hz),7.22-7.19 (1H, m), 6.97 (1H, d, J=8.5 Hz), 5.65 (1H, ddt, J=17.0, 10.2,6.3 Hz), 4.98 (1H, dd, J=10.2, 1.4 Hz), 4.88 (1H, dd, J=17.0, 1.4 Hz),4.75 (2H, d, J=6.3 Hz), 3.65 (211, t, J=5.5 Hz), 2.93-2.88 (4H, m),2.71-2.64 (4H, m), 2.61 (2H, t, J=5.5 Hz), 2.29 (3H, s).

ESI-MS Found: m/z [M+H]+ 487.

EXAMPLE 32 Production of2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

2.28 g of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,4-(4-methylpiperazin-1-yl)aniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 8.52 (1H, d, J=5.1 Hz),7.87-7.84 (2H, m), 7.46 (2H, d, J=8.6 Hz), 7.46 (1H, brs), 7.26-7.21(1H, m), 6.92 (2H, d, J=8.6 Hz), 5.71 (1H, ddt, J=17.2, 10.2, 5.9 Hz),5.02 (1H, d, J=10.2 Hz), 4.92 (1H, d, J=17.2 Hz), 4.78 (2H, d, J=5.9Hz), 3.23-3.20 (4H, m), 2.63-2.61 (4H, m), 2.38 (3H, s).

ESI-MS Found: m/z [M+H]+ 443.

EXAMPLE 33 Production of2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(6-methylpyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

11.6 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 29-1 to 29-2, for which, however,2-bromo-6-methylpyridine was used in place of 2-iodopyridine used inExample 29-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 7.79 (1H, dd, J=7.8, 7.4 Hz),7.64 (1H, d, J=8.2 Hz), 7.59 (1H, brs), 7.44 (1H, brs), 7.38 (1H, d,J=6.9 Hz), 7.20 (1H, d, J=8.2 Hz), 7.12 (1H, d, J=7.2 Hz), 5.96-5.66(1H, m), 5.02 (1H, d, J=10.4 Hz), 4.92 (1H, d, J=17.0 Hz), 4.78 (4H,brs), 3.03 (4H, brs), 2.65 (4H, brs), 2.60 (3H, s), 2.39 (3H, s).

ESI-MS Found: m/z [M+H]+ 487.

EXAMPLE 34 Production of6-(2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylpyridine-2-carboxamide

1.21 g of the entitled compound was obtained as a white solid in thesame manner as in Example 29-1 to 29-2, for which, however,6-bromo-N,N-dimethyl-2-pyridinecarboxamide was used in place of2-iodopyridine used in Example 29-1, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 8.01 (1H, d, J=9.0 Hz), 7.94(1H, dd, J=7.8, 7.6 Hz), 7.56 (1H, d, J=7.3 Hz), 7.47 (2H, brs), 7.31(1H, d, J=8.0 Hz), 7.03 (1H, d, J=8.6 Hz), 5.67 (1H, ddt, J=17.2, 9.6,6.3 Hz), 5.02 (1H, d, J=9.6 Hz), 4.94 (1H, d, J=17.2 Hz), 4.77 (2H, d,J=6.3 Hz), 3.16 (3H, s), 3.09 (3H, s), 2.96 (4H, t, J=4.6 Hz), 2.62 (4H,brs), 2.39 (3H, s), 2.33 (3H, s).

ESI-MS Found: m/z [M+H]+ 528.

EXAMPLE 35 Production of2-allyl-6-{[4-(4-hydroxypiperidin-1-yl)-3-methylphenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[1,4-d]pyrimidin-3-one

19.2 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,[4-(4-hydroxypiperidin-1-yl)-3-methylphenyl]aniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 8.53 (1H, d, J=3.2 Hz),7.83-7.91 (2H, m), 7.21-7.79 (3H, m), 7.00 (1H, d, J=7.3 Hz), 5.64-5.76(1H, m), 5.02 (1H, d, J=10.3 Hz), 4.92 (1H, d, J=17.1 Hz), 4.79 (2H, d,J=6.0 Hz), 3.81-3.91 (1H, m), 3.06-3.13 (2H, m), 2.68-2.79 (2H, m), 2.33(3H, s), 1.99-2.08 (2H, m), 1.70-1.80 (2H, m).

ESI-MS Found: m/z [M+H]+ 452.

EXAMPLE 36 Production of2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}(trifluoromethyl)pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

41.7 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,2-bromo-5-(trifluoromethyl)pyridine was used in place of 2-iodopyridineused in Example 29-1, and 3-methyl-4-(4-methylpiperazin-1-yl)aniline wasused in place of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol usedin Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.85 (1H, s), 8.77-8.75 (1H, m), 8.17 (1H, d,J=8.8 Hz), 8.01 (1H, dd, J=8.8, 1.8 Hz), 7.58-7.40 (2H, m), 7.31-7.25(1H, m), 7.05 (1H, d, J=8.5 Hz), 5.67 (1H, ddt, J=16.8, 10.2, 6.5 Hz),5.03 (1H, dd, J=10.2, 1.3 Hz), 4.95 (1H, dd, J=16.8, 1.3 Hz), 4.84 (2H,d, J=6.5 Hz), 3.00-2.94 (4H, m), 2.72-2.53 (4H, m), 2.40 (3H, s), 2.34(3H, s).

ESI-MS Found: m/z [M+H]+ 525.

EXAMPLE 37 Production of2-allyl-6-{[3-methyl-4-(1-methylpiperidin-4-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of 1-(4-bromo-3-methylphenyl)-2,5-dimethyl-1H-pyrrole

Acetic acid (30 mL) solution of 9.30 g of 4-bromo-3-methylaniline and6.85 g of 2,5-hexanedione was stirred at 80° C. for 5 hours. Thereaction liquid was concentrated, aqueous saturated sodiumhydrogencarbonate solution was added thereto, extracted with ethylacetate, washed with saturated saline water, and dried with anhydrousmagnesium sulfate. This was filtered through silica gel columnchromatography (ethyl acetate), the solvent was concentrated, hexane wasadded to it, and the formed solid was collected to obtain 10.90 g of theentitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.60 (1H, d, J=8.2 Hz), 7.08 (1H, d, J=2.5Hz), 6.91 (1H, dd, J=8.3, 2.4 Hz), 5.89 (2H, s), 2.44 (3H, s), 2.02 (6H,s).

ESI-MS Found: m/z [M+H]+ 264, 266.

2) Production of tert-butyl4-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-methylphenyl]-4-hydroxypiperidine-1-carboxylate

Tetrahydrofuran (52 mL) solution of 2.64 g of the compound obtained inthe above 1 was cooled in a dry ice/acetone bath, and at −65° C. orlower, 4.14 mL of 2.66 M n-butyllithium/hexane solution was addedthereto. After this was stirred for 15 minutes, tetrahydrofuran (10 mL)solution of 2.0 g of 1-tert-butoxycarbonylpiperidin-4-one was addedthereto at −65° C. or lower. After this was stirred for 10 minutes,water was added thereto and heated up to room temperature, extractedwith ethyl acetate, washed with saturated saline water, and dried withanhydrous magnesium sulfate. The solvent was evaporated away, theresidue was purified through silica gel column chromatography(hexane/ethyl acetate) to obtain 3.19 g of the entitled compound.

¹H-NMR (400 MHz, CDCl₃) δ: 7.42 (1H, d, J=8.4 Hz), 7.01 (1H, s), 7.00(1H, d, J=8.4 Hz), 5.88 (2H, s), 4.05 (2H, brs), 3.31 (2H, brs), 2.64(3H, s), 2.18-1.96 (4H, m), 2.03 (6H, s), 1.48 (9H, s).

ESI-MS Found: m/z [M+H]+ 385.

3) Production of tert-butyl4-(4-amino-2-methylphenyl)-3,6-dihydropyridin-1(2H)-carboxylate

4.5 mL of aqueous 50% hydroxylamine solution and 10 mL of 4 Nhydrochloric acid were added to ethanol (26 mL) solution of 2.64 g ofthe compound obtained in the above 2, and stirred at 90° C. for 2 days.The reaction liquid was concentrated, aqueous sodium hydrogencarbonatesolution was added thereto, and extracted with ethyl acetate. This waswashed with saturated saline water, dried with anhydrous magnesiumsulfate, the solvent was evaporated away, and the residue was purifiedthrough silica gel column chromatography (hexane/ethyl acetate) andthrough basic silica gel column chromatography (hexane/ethyl acetate) toobtain 401 mg of the entitled compound as an amorphous substance.

¹H-NMR (400 MHz, CDCl₃) δ: 6.87 (1H, d, J=7.8 Hz), 6.51 (1H, s), 6.48(1H, dd, J=8.0; 2.4 Hz), 5.49 (1H, brs), 4.00 (2H, brs), 3.59 (4H, t,J=5.4 Hz), 3.52 (2H, brs), 2.30 (2H, brs), 2.19 (3H, s), 1.50 (9H, s).

ESI-MS Found: m/z [M+H]+ 275.

4) Production of tert-butyl4-(4-amino-2-methylphenyl)piperidine-1-carboxylate

In a nitrogen atmosphere, 100 mg of 10% palladium-carbon was added totetrahydrofuran (2 mL)-methanol (2 mL) solution of 400 mg of thecompound obtained in the above 3, and stirred in a hydrogen atmospherefor 4 hours. The reaction system was purged with nitrogen, the catalystwas removed through filtration, and the filtrate was concentrated toobtain 219 mg of the entitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.00 (1H, d, J=7.8 Hz), 6.68-6.64 (2H, m),4.24 (2H, brs), 2.79-2.75 (3H, m), 2.28 (3H, s), 1.72-1.54 (4H, m), 1.48(9H, s).

ESI-MS Found: m/z [M+H]+ 277.

5) Production of2-allyl-6-{[3-methyl-4-(1-methylpiperidin-4-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

With cooling with ice, tetrahydrofuran (1 mL) solution of 60 mg of thecompound obtained in the above 4 was added to tetrahydrofuran (2 mL)solution of 20 mg of lithiumaluminium hydride. The reaction liquid washeated at 60° C., and stirred for 1 hour and 40 minutes. The reactionliquid was restored to room temperature, and 0.05 mL of 4 N sodiumhydroxide solution and 0.1 mL of water were added thereto, and theprecipitated solid was taken out through filtration. The solvent wasconcentrated, and crude 3-methyl-4-(1-methylpiperidin-4-yl)aniline wasobtained.

In the same manner as in Example 29-1 to 29-2, 32.7 mg of the entitledcompound was obtained as a white solid, for which, however, the crude3-methyl-4-(1-methylpiperidin-4-yl)aniline obtained in the abovereaction was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 8.56-8.53 (1H, m), 7.91-7.85(2H, m), 7.43-7.37° (3H, m), 7.22 (1H, d, J=8.2 Hz), 7.64 (1H, brs),7.46-7.42 (2H, m), 7.19 (1H, d, J=8.2 Hz), 5.68 (1H, ddt, J=16.4, 10.4,6.3 Hz), 5.02 (1H, d, J=10.4 Hz), 4.92 (1H, d, J=16.4 Hz), 4.79 (2H, d,J=6.3 Hz), 3.03 (2H, d, J=11.4 Hz), 2.74-2.62 (1H, m), 2.37 (3H, s),2.35 (3H, s), 2.18-2.07 (2H, m), 1.94-1.73 (4H, m).

ESI-MS Found: m/z [M+H]+ 456.

EXAMPLE 38 Production of2-allyl-6-({4-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methylphenyl}amino)-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of tert-butyl4-{4-[(2-allyl-3-oxo-1-pyridin-2-yl-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino]-2-methylphenyl}piperidine-1-carboxylate

72 mg of the entitled compound was obtained as a white solid in the samemanner as in Example 29-1 to 29-2, for which, however, tert-butyl4-(4-amino-2-methylphenyl)piperidine-1-carboxylate obtained in Example37-4 was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.85 (1H, s), 8.54 (1H, dd, J=4.9, 1.5 Hz),7.90-7.85 (2H, m), 7.46 (2H, brs), 7.37 (1H, d, J=9.2 Hz), 7.15 (1H, d,J=8.8 Hz), 5.69 (1H, ddt, J=16.4, 10.4, 6.3 Hz), 5.02 (1H, d, J=10.4Hz), 4.92 (1H, d, J=16.4 Hz), 4.79 (2H, d, J=6.3 Hz), 4.34-4.22 (2H, m),2.89-2.78 (3H, m), 2.37 (3H, s), 1.80-1.54 (4H, m), 1.50 (9H, s).

ESI-MS Found: m/z [M+H]+ 542.

2) Production of2-allyl-6-[(3-methyl-4-piperidin-4-ylphenyl)amino]-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

1 mL of trifluoroacetic acid was added to the compound obtained in theabove 1, stirred, and aqueous potassium carbonate solution was added toit, and extracted with a mixed solvent of chloroform and isopropanol.This was dried with anhydrous magnesium sulfate, and the solvent wasevaporated away under reduced pressure to obtain 34 mg of the entitledcompound as a white solid.

¹H-NMR (CD3OD) δ: 8.87 (1H, s), 8.57-8.56 (1H, m), 8.08-8.04 (1H, m),7.95 (1H, d, J=8.2 Hz), 7.64 (1H, brs), 7.46-7.42 (2H, m), 7.19 (1H, d,J=8.2 Hz), 5.76 (1H, ddt, J=18.6, 10.2, 6.1 Hz), 5.08 (1H, d, J=10.2Hz), 4.97 (1H, d, J=18.6 Hz), 4.75 (2H, d, J=6.1 Hz), 3.49-3.45 (2H, m),3.17-3.10 (2H, m), 2.40 (3H, s), 2.01-1.85 (4H, m).

ESI-MS Found: m/z [M+H]+ 442.

3) Production of2-allyl-6-({4-[1-(2-hydroxyethyl)piperidin-4-yl]-3-methylphenyl}amino)-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

A mixed methanol solution (1 mL) of 0.3 M sodium borocyanohydride and0.15 M zinc chloride was added to a tetrahydrofuran (1 mL) solution of34 mg of the compound obtained in the above 2) and 20 mg ofglycoaldehyde dimer. This was stirred at room temperature for 5 minutes,saturated sodium hydrogencarbonate was added thereto, and extracted withethyl acetate. This was washed with saturated saline water, dried withanhydrous magnesium sulfate, the solvent was evaporated away, and theresidue was purified through basic silica gel column chromatography(chloroform-methanol) to obtain the entitled compound (20.2 mg) as awhite solid.

¹H-NMR (CDCl₃) δ: 8.85 (1H, s), 8.54 (1H, dt, J=4.9, 1.5 Hz), 7.90-7.87(2H, m), 7.44 (2H, brs), 7.38 (1H, dd, J=8.8, 2.4 Hz), 7.20 (1H, d,J=8.3 Hz), 5.74-5.64 (1H, m), 5.02 (1H, dd, J=10.2, 1.5 Hz), 4.92 (1H,dd, J=17.1, 1.0 Hz), 4.79 (2H, d, J=6.3 Hz), 3.67 (2H, t, J=5.4 Hz),3.09 (2H, d, J=11.2 Hz), 2.78-2.68 (1H, m), 2.62 (2H, dd, J=5.4, 4.9Hz), 2.36 (3H, s), 2.30-2.20 (2H, m), 1.84-1.75 (4H, m).

ESI-MS Found: m/z [M+H]+ 486.

EXAMPLE 39 Production of2-allyl-6-{[4-(4-cyclopropylpiperazin-1-yl)-3-methylphenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

33.2 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,4-(4-cyclopropyl-1-piperazinyl)-3-methylaniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 8.53 (1H, d, J=2.8 Hz),7.82-7.93 (2H, m), 6.98-7.62 (4H, m), 5.64-5.75 (1H, m), 5.01 (1H, s,J=9.9 Hz), 4.92 (1H, d, J=17.0 Hz), 4.78 (2H, d, J=5.8 Hz), 2.90 (4H,bs), 2.80 (4H, bs), 2.34 (3H, s), 1.72 (1H, bs), 0.50 (4H, bs).

ESI-MS Found: m/z [M+H]+ 483.

EXAMPLE 40 Production of2-allyl-6-{[4-(4-cyclobutylpiperazin-1-yl)-3-methylphenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

36.6 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,4-(4-cyclobutyl-1-piperazinyl)-3-methylaniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 8.52 (1H, d, J=3.2 Hz),7.82-7.94 (2H, m), 7.01-7.62 (4H, m), 5.63-5.76 (1H, m), 5.01 (1H, d,J=10.1 Hz), 4.92 (1H, d, J=17.1 Hz), 4.78 (2H, d, J=5.9 Hz), 2.95 (4H,bs), 2.56 (4H, bs), 2.80-2.89 (1H, m), 2.32 (3H, s), 1.68-2.13 (6H, m).

ESI-MS Found: m/z [M+H]+ 497.

EXAMPLE 41 Production of2-allyl-6-{[4-(4-ethylpiperazin-1-yl)-3-methylphenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

19 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,4-(4-ethyl-1-piperazinyl)-3-methylaniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 8.53 (1H, d, J=3.2 Hz),7.83-7.92 (2H, m), 7.01-7.70 (4H, m), 5.63-5.76 (1H, m), 5.01 (1H, d,J=10.1 Hz), 4.91 (1H, d, J=16.9 Hz), 4.78 (2H, d, J=6.8 Hz), 2.96 (4H,bs), 2.63 (4H, bs), 2.52 (2H, q, J=7.5 Hz), 2.33 (3H, s), 1.15 (3H, t,J=4.5 Hz).

ESI-MS Found: m/z [M+H]+ 471.

EXAMPLE 42 Production of2-allyl-6-{[4-(4-isopropylpiperazin-1-yl)-3-methylphenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

17.5 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,4-(4-isopropyl-1-piperazinyl)-3-methylaniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 8.53 (1H, d, J=3.5 Hz),7.82-7.91 (2H, m), 7.01-7.57 (4H, m), 5.64-5.73 (1H, m), 5.02 (1H, d,J=10.5 Hz), 4.91 (1H, d, J=17.5 Hz), 4.78 (2H, d, J=7.2 Hz), 2.97 (4H,bs), 2.73 (5H, m), 2.33 (3H, s), 1.13 (6H, d, J=5.2 Hz).

ESI-MS Found: m/z [M+H]+ 485.

EXAMPLE 43 Production of2-allyl-6-{[4-(4-methylpiperazin-1-yl)-phenyl]amino}-1-(6-methylpyridin-2-yl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

15.8 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,2-bromo-6-methylpyridine was used in place of 2-iodopyridine used inExample 29-1, and 4-(4-methyl-1-piperazinyl)aniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.85 (1H, s), 7.76 (1H, dd, J=8.0, 7.6 Hz),7.66 (1H, d, J=8.0 Hz), 7.51 (2H, d, J=8.8 Hz), 7.48 (1H, brs), 7.12(1H, d, J=7.4 Hz), 6.95 (2H, d, J=8.8 Hz), 5.73 (1H, ddt, J=17.0, 10.2,6.7 Hz), 5.05 (1H, d, J=10.2 Hz), 4.93 (1H, d, J=17.0 Hz), 4.80 (2H, d,J=6.7 Hz), 3.24 (4H, t, J=4.9 Hz), 2.66-2.62 (4H, m), 2.62 (3H, s), 2.42(3H, s).

ESI-MS Found: m/z [M+H]+ 457.

EXAMPLE 44 Production of2-allyl-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

10.2 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 29-1 to 29-2, for which, however,4-(1-methyl-4-piperidinyl)aniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.85 (1H, s), 8.53 (1H, d, J=5.3 Hz),7.87-7.83 (2H, m), 7.52 (2H, d, J=8.6 Hz), 7.52 (1H, brs), 7.21 (2H, d,J=8.6 Hz), 5.69 (1H, ddt, J=17.0, 10.4, 6.5 Hz), 5.02 (1H, d, J=10.4Hz), 4.92 (1H, d, J=17.0 Hz), 4.79 (2H, d, J=6.5 Hz), 3.00 (2H, d,J=11.0 Hz), 2.50-2.44 (1H, m), 2.35 (1H, s), 2.11-2.04 (2H, m),1.86-1.80 (4H, m).

ESI-MS Found: m/z [M+H]+ 442.

EXAMPLE 45 Production of2-allyl-6-{[4-(1-ethylpiperidin-4-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

14.5 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 29-1 to 29-2, for which, however,4-(1-ethyl-4-piperidinyl)aniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.86 (1H, s), 8.53 (1H, d, J=4.9 Hz),7.87-7.83 (2H, m), 7.52 (2H, d, J=8.4 Hz), 7.50 (1H, brs), 7.22 (2H, d,J=8.4 Hz), 5.69 (1H, ddt, J=17.0, 10.2, 6.3 Hz), 5.02 (1H, d, J=10.2Hz), 4.92 (1H, dd, J=17.0, 1.2 Hz), 4.79 (2H, d, J=6.3 Hz), 3.11 (2H, d,J=11.4 Hz), 2.49-2.47 (3H, m), 2.05-1.95 (2H, m), 1.90-1.80 (4H, m),1.15 (3H, t, J=7.2 Hz).

ESI-MS Found: m/z [M+H]+ 456.

EXAMPLE 46 Production of2-allyl-6-{[4-[1-(2-hydroxyethyl)piperidin-4-yl]phenyl}amino)-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

16 mg of the entitled compound was obtained as a white solid in the samemanner as in Example 29-1 to 29-2, for which, however,2-[4-(4-aminophenyl)-1-piperidinyl]ethanol was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.86 (1H, s), 8.54 (1H, t, J=4.7 Hz),7.89-7.87 (2H, m), 7.53 (2H, d, J=8.6 Hz), 7.47 (1H, brs), 7.21 (2H, d,J=7.6 Hz), 5.69 (1H, ddt, J=17.0, 10.0, 6.5 Hz), 5.02 (1H, d, J=10.0Hz), 4.92 (1H, dd, J=17.0, 1.3 Hz), 4.79 (2H, d, J=6.5 Hz), 3.67 (2H, t,J=5.1 Hz), 3.08 (2H, d, J=12.1 Hz), 2.62 (2H, t, J=5.5 Hz), 2.57-2.51(1H, m), 2.23 (2H, t, J=10.9 Hz), 1.89-1.78 (2H, m).

ESI-MS Found: m/z [M+H]+ 472.

EXAMPLE 47 Production of2-allyl-6-({3-methyl-4-[(1-methylpiperidin-4-yl)amino]phenyl}amino)-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

11 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,2-methyl-N¹-(1-methyl-4-piperidinyl)-1,4-benzenediamine was used inplace of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used inExample 29-2.

¹H-NMR (400 MHz, CD₃OD) δ: 8.78 (1H, s), 8.54 (1H, d, J=4.8 Hz), 8.01(1H, dd, J=7.2, 7.2 Hz), 7.92 (1H, d, J=7.2 Hz), 7.43 (1H, s, J=2.0 Hz),7.40 (1H, dd, J=4.8, 3.2 Hz), 7.27 (1H, dd, J=8.4, 2.0 Hz), 6.6 (1H, d,J=8.4 Hz), 5.74 (1H, ddd, J=18.4, 14.8, 10.0 Hz), 5.07 (1H, d, J=10.0Hz), 4.95 (1H, d, J=18.4 Hz), 4.73 (2H, J=14.8 Hz), 4.37 (2H, d, J=4.7Hz), 3.36-3.24 (1H, m), 2.89-2.75 (2H, m), 2.31 (3H, s), 2.23-2.12 (2H,m), 2.10-2.02 (5H, m), 1.60-1.45 (2H, m).

ESI-MS Found: m/z [M+H]+ 471.

EXAMPLE 48 Production of2-allyl-6-{[4-(4-ethylpiperazin-1-yl)-3-(hydroxymethyl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

57 mg of the entitled compound was obtained as a white solid in the samemanner as in Example 29-1 to 29-2, for which, however,[5-amino-2-(4-ethylpiperazin-1-yl)phenyl]methanol was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.85 (1H, s), 8.54 (1H, d, J=4.4 Hz),7.93-7.83 (2H, m); 7.60 (1H, brs), 7.52 (1H, brs), 7.35 (1H, d, J=8.8Hz), 7.26-7.20 (1H, m), 5.68 (1H, ddt, J=17.1, 10.2, 6.4 Hz), 5.02 (1H,dd, J=10.2, 1.0 Hz), 4.91 (1H, dd, J=17.1, 1.5 Hz), 4.82-4.77 (5H, m),3.04 (4H, t, J=4.6 Hz), 2.67 (4H, brs), 2.52 (2H, d, J=6.8 Hz), 1.15(3H, t, J=7.1 Hz).

ESI-MS Found: m/z [M+H]+ 487.

EXAMPLE 49 Production of2-allyl-1-(6-aminopyridin-2-yl)-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of di-tert-butyl{6-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]-2-pyridinyl}imidedicarboxylate

2.00 g of the entitled compound was obtained as a white solid in thesame manner as in Example 29-1, for which, however, di-tert-butyl(6-bromopyridin-2-yl)imidedicarboxylate was sued in place of2-iodopyridine used in Example 29-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.92 (1H, s), 7.92 (1H, t, J=8.0 Hz), 7.80(1H, d, J=8.8 Hz), 7.35 (1H, d, J=7.8 Hz), 5.63 (1H, ddt, J=17.1, 10.2,6.3 Hz), 5.03 (1H, dd, J=10.2, 1.0 Hz), 5.00 (1H, dd, J=17.1, 1.2 Hz),4.82 (2H, d, J=6.3 Hz), 2.58 (3H, s), 1.51 (18H, s).

ESI-MS Found: m/z [M+H]+ 515.

2) Production of2-allyl-1-(6-aminopyridin-2-yl)-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

53 mg of m-chloroperbenzoic acid (>65%) was added to toluene (2 mL)solution of 103 mg of di-tert-butyl{6-[2-allyl-6-(methylthio)-3-oxo-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-2-pyridinyl}imidedicarboxylate,and stirred for 30 minutes. 0.105 mL of N,N-diisopropylethylamine and 49mg of 3-methyl-4-(4-methylpiperazin-1-yl)aniline were added to thereaction liquid, and stirred overnight. Aqueous saturated sodiumhydrogencarbonate solution was added to the reaction liquid, ethylacetate was added thereto for extraction, the resulting extract waswashed with saturated saline water, and dried with anhydrous magnesiumsulfate. The solvent was evaporated away, and the residue was purifiedthrough basic silica gel column chromatography (hexane/ethyl acetate=1/1to 0/1). After concentrated, 93.2 mg of a white solid was obtained.

2 mL of trifluoroacetic acid was added to the obtained compound,stirred, and saturated sodium hydrogencarbonate was added thereto,extracted with ethyl acetate, washed with saline water, and dried withanhydrous magnesium sulfate. The solvent was evaporated away underreduced pressure to obtain 51.8 mg of the entitled compound as a whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.60 (1H, t, J=7.8 Hz), 7.52(1H, s), 7.34 (1H, dd, J=8.8, 2.4 Hz), 7.00 (1H, d, J=8.3 Hz), 6.43 (1H,d, J=7.8 Hz), 5.71 (1H, ddt, J=16.8, 10.2, 5.9 Hz), 5.06 (1H, dd,J=10.2, 1.0 Hz), 5.00 (1H, dd, J=16.8, 1.2 Hz), 4.71 (2H, d, J=5.9 Hz),4.58 (2H, s), 2.95 (4H, t, J=4.6 Hz), 2.66 (4H, s), 2.42 (3H, s), 2.31(3H, s).

ESI-MS Found: m/z [M+H]+ 412.

EXAMPLE 50 Production of2-allyl-1-(6-aminopyridin-2-yl)-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

966 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 49-1 to 49-2, for which, however,4-(4-methylpiperazin-1-yl)aniline was used in place of3-methyl-4-(4-methylpiperazin-1-yl)aniline used in Example 49-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.59 (1H, t, J=7.8 Hz), 7.39(1H, brs), 6.91 (2H, d, J=8.8 Hz), 6.42 (1H, d, J=8.3 Hz), 5.71 (1H,ddt, J=17.1, 10.2, 5.9 Hz), 5.06 (1H, dd, J=10.2, 1.0 Hz), 5.00 (1H, dd,J=17.1, 1.0 Hz), 4.70 (2H, d, J=5.9 Hz), 4.57 (2H, s), 3.20 (4H, t,J=5.1 Hz), 2.61 (4H, t, J=4.9 Hz), 2.38 (3H, s).

ESI-MS Found: m/z [M+H]+ 458.

EXAMPLE 51 Production of2-allyl-1-{6-[(dimethylamino)methyl]pyridin-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of2-allyl-1-[6-(hydroxymethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

3.40 g of the entitled compound was obtained as a white solid in thesame manner as in Example 29-1, for which, however,(6-bromopyridin-2-yl)methanol was used in place of 2-iodopyridine usedin Example 29-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.94 (1H, s), 7.91 (1H, t, J=7.8 Hz), 7.78(1H, dd, J=8.0, 0.7 Hz), 7.27 (1H, d, J=7.8 Hz), 5.76-5.66 (1H, m), 5.07(1H, dd, J=10.2, 1.0 Hz), 4.95 (1H, dd, J=17.1, 1.0 Hz), 4.84-4.77 (4H,m), 2.58 (3H, s).

ESI-MS Found: m/z [M+H]+ 330.

2) Production of2-allyl-1-{6-[(dimethylamino)methyl]-2-pyridinyl}-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onehydrochloride

1.16 mL of triethylamine and 0.451 mL of methanesulfonyl chloride wereadded to tetrahydrofuran (20 mL) solution of 1.37 g of the compoundobtained in the above 1, and stirred for 30 minutes, and then 6 mL of2.0 M dimethylamine/tetrahydrofuran solution was added to the reactionliquid and stirred for 8 hours. Water was added to the reaction liquid,and extracted with ethyl acetate. This was washed with saturated salinewater, dried with anhydrous magnesium sulfate, and concentrated underreduced pressure. 10 mL of ethyl acetate and 1.5 mL of 4 N hydrochloricacid-dioxane solution were added to the resulting residue, then thesolvent was concentrated under reduced pressure, and the residue wascrystallized with methanol/diethyl ether to obtain 1.50 g of theentitled compound as a white solid.

¹H-NMR (400 MHz, DMSO-d₆) δ: 8.17 (1H, s), 7.36 (1H, t, J=7.8 Hz), 7.21(1H, d, J=7.8 Hz), 6.76 (1H, d, J=7.3 Hz), 4.92 (1H, ddt, J=17.1, 10.2,6.0 Hz), 4.26 (1H, dd, J=10.2, 1.5 Hz), 4.14 (1H, dd, J=17.1, 1.5 Hz),4.00 (2H, dt, J=6.0, 1.3 Hz), 3.75 (2H, s), 2.14 (6H, s), 1.78 (3H, s).

ESI-MS Found: m/z [M+H]+ 357.

3) Production of2-allyl-1-{6-[(dimethylamino)methyl]pyridin-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

65 mg of m-chloroperbenzoic acid was added to N,N-dimethylformamide (2mL) solution of 100 mg of the compound obtained in the above 2, andstirred at room temperature for 15 minutes. The reaction liquid waswashed with aqueous saturated sodium hydrogencarbonate solution, anddried with anhydrous sodium sulfate. The solvent was evaporated awayunder reduced pressure to obtain crude2-allyl-1-{6-[(dimethylamino)methyl]pyridin-2-yl}-6-(methylsulfinyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneas a white solid.

40 mg of 4-(4-methylpiperazin-1-yl)aniline and 0.1 mL ofN,N-diisopropylethylamine were added in that order todimethylsulfoxide/toluene (1/10, 10 mL) solution of 40 mg of the abovecompound, and stirred at 120° C. for 15 hours. The solvent wasevaporated away under reduced pressure, water was added thereto,extracted with ethyl acetate, and dried with anhydrous sodium sulfate.The solvent was evaporated away under reduced pressure, and the residuewas separated and purified through basic silica gel columnchromatography (ethyl acetate) to obtain 8.4 mg of the entitled compoundas a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.82 (1H, t, J=7.8 Hz), 7.74(1H, d, J=7.8 Hz), 7.47 (2H, d, J=8.8 Hz), 7.39 (1H, d, J=7.3 Hz), 6.92(2H, d, J=6.3 Hz), 5.74-5.63 (1H, m), 5.00 (1H, dd, J=10.2, 1.0 Hz),4.89 (1H, dd, J=17.1, 1.0 Hz), 4.80 (2H, d, J=5.9 Hz), 3.64 (2H, s),3.22 (41-1, t, J=4.9 Hz), 2.64 (4H, d, J=4.4 Hz), 2.39 (3H, s), 2.34(6H, s).

ESI-MS Found: m/z [M+H]+ 500.

EXAMPLE 52 Production of2-allyl-1-{6-[(dimethylamino)methyl]pyridin-2-yl}-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

682 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 51-1 to 51-2, for which, however,3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 51.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.83 (1H, t, J=7.8 Hz), 7.77(1H, d, J=7.8 Hz), 7.50 (1H, s), 7.39 (1H, brs), 7.38 (1H, d, J=7.8 Hz),7.32 (1H, dd, J=8.5, 2.7 Hz), 7.02 (1H, d, J=8.8 Hz), 5.68 (1H, ddt,J=17.1, 10.2, 6.3 Hz), 5.00 (1H, dd, J=10.2, 1.0 Hz), 4.89 (1H, dd,J=17.1, 1.0 Hz), 4.81 (2H, d, J=6.3 Hz), 3.62 (2H, s), 2.95 (4H, t,J=4.6 Hz), 2.61 (4H, s), 2.39 (3H, s), 2.33 (6H, s), 2.32 (3H, s).

ESI-MS Found: m/z [M+H]+ 524.

EXAMPLE 53 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

1) Production of 2-(6-bromo-2-pyridinyl)-2-propanol

In a nitrogen atmosphere, 30 mL of 3 M methylmagnesium iodide/diethylether was added to 300 mL of diethyl ether solution of 8.72 g of methyl6-bromopyridine-2-carboxylate. Water and 2 N hydrochloric acid wereadded to the reaction liquid, and extracted with ethyl acetate. This waswashed with aqueous saturated sodium hydrogencarbonate solution andsaturated saline water, and dried with anhydrous magnesium sulfate. Thesolvent was evaporated away under reduced pressure to obtain 8.51 g ofcrude 2-(6-bromo-2-pyridinyl)-2-propanol as a yellow oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.56 (1H, t, J=7.8 Hz), 7.38 (1H, dd, J=7.8,1.0 Hz), 7.36 (1H, dd, J=7.8, 1.0 Hz), 1.55 (6H, s).

ESI-MS Found: m/z [M+H]+ 216, 218.

2) Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

12.89 g of the entitled compound was obtained in the same manner as inExample 29-1, for which, however, the compound obtained in the abovereaction was used in place of 2-iodopyridine used in Example 29-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.95 (1H, s), 7.91 (1H, t, J=8.0 Hz), 7.76(1H, d, J=7.3 Hz), 7.40 (1H, dd, J=7.8, 1.0 Hz), 5.70 (1H, ddt, J=17.1,10.2, 6.3 Hz), 5.06 (1H, dd, J=10.2, 1.0 Hz), 4.93 (1H, dd, J=17.1, 1.2Hz), 4.81 (2H, d, J=6.3 Hz), 2.59 (4H, s), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+: 358.

3) Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

817 mg of m-chloroperbenzoic acid (>65%) was added to toluene (20 mL)solution of 1.10 g of the above produce, and stirred fro 20 minutes.1.61 mL of N,N-diisopropylethylamine and 706 mg of4-(4-methylpiperazin-1-yl)aniline were added to the reaction liquid, andstirred overnight. Aqueous saturated sodium hydrogencarbonate solutionwas added to the reaction liquid, extracted with ethyl acetate, washedwith saturated saline water, and dried with anhydrous magnesium sulfate.The solvent was evaporated away, and the residue was purified throughbasic silica gel column chromatography (hexane/ethyl acetate=1/1 to 0/1,ethyl acetate/ethanol=98/2). After concentrated, this was recrystallizedfrom ethyl acetate to obtain 1.20 g of the entitled compound as a yellowsolid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.86 (1H, dd, J=8.0, 7.8 Hz),7.75 (1H, d, J=7.3 Hz), 7.49 (1H, brs), 7.48 (2H, d, J=9.0 Hz), 7.34(1H, d, J=7.4 Hz), 6.93 (2H, d, J=9.0 Hz), 5.70 (1H, ddt, J=17.2, 10.0,6.5 Hz), 5.04 (1H, d, J=10.0 Hz), 4.94 (1H, d, J=17.2 Hz), 4.74 (2H, d,J=6.5 Hz), 3.26 (4H, t, J=4.8 Hz), 2.73 (4H, brs), 2.44 (3H, s), 1.59(6H, s).

ESI-MS Found: m/z [M+H]+ 501.

4) Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onemonohydrate

To a stirred solution of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(2.17 g, 92.2 wt %, 2.00 g assay, 5.60 mmol) in toluene (30 mL) wasadded m-chloroperbenzoic acid (1.66 g) below 30° C. and the mixture wasstirred at the same temperature for 30 minutes. ThenN,N-diisopropylethylamine (2.92 mL) and4-(4-methylpiperazin-1-yl)aniline (1.19 g) were added below 30° C. andthe slurry was stirred at ambient temperature for more than 2 hours.Then toluene (30 mL) and isopropanol (50 mL) were added, and washed withaqueous 1N sodium hydroxide solution (20 mL) and 15% aqueous sodiumchloride solution (10 mL). The aqueous layer was extracted with toluene(20 mL). The combined organic layers were concentrated to 40 mL andisopropanol (40 mL) was added. The mixture was concentrated to 40 mL andaged at ambient temperature for overnight. The crystal was collected byfiltration, washed with isopropanol (20 mL) and dried in vacuo atambient temperature for overnight to obtain the isopropanol solvate(2.99 g, 75.6 wt %) as a pale yellowish crystal in 81% yield.

Above isopropanol solvate (10.20 g, 78.4 wt %, 8.00 g assay, 15.98 mol)was dissolved in a mixture of ethanol (120 mL) and water (60 mL) at 50°C., and ethanol-water (2:1) (60 mL) was added. To the resulting solutionwas added water (160 mL) while keeping the temperature over 45° C. andthe seed (80 mg) was added at 50° C. After aged at the same temperaturefor 1 hour, water (160 mL) was added over 1 hour at 50° C. Then theslurry was cooled to ambient temperature and aged for overnight. Afteraged below 5° C. for 1 hour, the crystal was collected by filtration,washed with ethanol-water (1:2.5) (80 mL) and dried in vacuo at ambienttemperature for overnight to obtain2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onemonohydrate (7.97 g, 95.6 wt %) as a pale yellowish crystal in 95%yield. Melting Point: 124-126° C.

EXAMPLE 54 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

56.8 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 53-1 to 53-3, for which, however,methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (DMSO-d₆) δ: 10.18 (1H, brs), 8.82 (1H, s), 8.02 (1H, t, J=7.8Hz), 7.77 (1H, d, J=8.4 Hz), 7.67 (1H, brs), 7.62 (1H, d, J=8.2 Hz),7.40 (1H, d, J=6.8 Hz), 6.99 (1H, d, J=8.6 Hz), 5.66 (1H, ddt, J=17.2,10.4, 6.1 Hz), 5.33 (1H, s), 4.99 (1H, d, J=10.4 Hz), 4.81 (1H, d,J=17.2 Hz), 4.68 (2H, d, J=6.1 Hz), 2.82 (411, brs), 2.50 (4H, brs),2.25 (6H, s), 1.46 (6H, s).

ESI-MS Found: m/z [M+H]+ 525.

EXAMPLE 55 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

48 mg of the entitled compound was obtained as a white solid in the samemanner as in Example 53-1 to 53-3, for which, however,[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.86 (1H, s), 7.92 (1H, t, J=8.0 Hz), 7.76(1H, d, J=7.8 Hz), 7.60 (1H, s), 7.37 (2H, d, J=7.8 Hz), 7.22 (1H, d,J=8.8 Hz), 5.70 (1H, ddt, J=17.1, 10.2, 6.3 Hz), 5.04 (1H, d, J=10.2Hz), 4.93 (1H, d, J=17.1 Hz), 4.79 (2H, s), 4.75 (2H, d, J=6.3 Hz), 3.03(4H, t, J=5.0 Hz), 2.65 (4H, s), 2.40 (3H, s), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 531.

EXAMPLE 56 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

60.2 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-(1-methyl-4-piperidinyl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.86 (1H, s), 7.87 (1H, t, J=8.2 Hz), 7.76(1H, d, J=8.2 Hz), 7.53 (2H, d, J=8.4 Hz), 7.52 (1H, brs), 7.36 (1H, d,J=7.6 Hz), 7.22 (1H, d, J=8.6 Hz), 5.70 (1H, ddt, J=16.8, 10.3, 6.3 Hz),5.05 (1H, d, J=10.3 Hz), 4.94 (1H, d, J=16.8 Hz), 4.75 (2H, d, J=6.3Hz), 3.94 (1H, brs), 3.01 (1H, d, J=11.5 Hz), 2.49-2.47 (1H, m), 2.35(3H, s), 2.08-2.04 (2H, m), 1.86-1.80 (2H, m), 1.70-1.60 (2H, m), 1.59(6H, s).

ESI-MS Found: m/z [M+H]+ 500.

EXAMPLE 57 Production of2-allyl-6-{[4-(4-tert-butylpiperazin-1-yl)phenyl]amino}-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

43 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-(4-tert-butyl-1-piperazinyl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.85 (1H, t, J=7.8 Hz), 7.76(1H, d, J=7.3 Hz), 7.45 (2H, d, J=8.8 Hz), 7.33 (1H, d, J=8.3 Hz), 6.93(2H, d, J=9.3 Hz), 5.76-5.65 (1H, m), 5.04 (1H, d, J=10.2 Hz), 4.94 (1H,dd, J=17.1, 1.5 Hz), 4.74 (2H, d, J=6.3 Hz), 3.21 (4H, brs), 2.78 (4H,brs), 1.58 (9H, s).

ESI-MS Found: m/z [M+H]+ 543.

EXAMPLE 58 Production of2-allyl-6-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

50.3 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-(4-ethyl-1-piperazinyl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.85 (1H, t, J=7.8 Hz), 7.76(1H, d, J=7.8 Hz), 7.46 (2H, d, J=8.8 Hz), 7.34 (1H, d, J=8.3 Hz), 6.93(2H, d, J=8.8 Hz), 5.76-5.64 (1H, m), 5.04 (1H, dd, J=10.2, 1.0 Hz),4.94 (1H, dd, J=17.1, 1.0 Hz), 4.75 (2H, d, J=6.3 Hz), 4.00 (1H, brs),3.23 (4H, t, J=4.9 Hz), 2.65 (4H, t, J=4.9 Hz), 2.51 (2H, q, J=7.3 Hz),1.59 (6H, s), 1.16 (3H, t, J=7.3 Hz).

ESI-MS Found: m/z [M+H]+ 515.

EXAMPLE 59 Production of2-allyl-6-{[4-(4-isopropylpiperazin-1-yl)phenyl]amino}-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

32.1 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-(4-isopropyl-1-piperazinyl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.85 (1H, t, J=8.0 Hz), 7.75(1H, d, J=8.3 Hz), 7.46 (2H, d, J=8.8 Hz), 7.33 (1H, d, J=7.8 Hz), 6.93(2H, d, J=9.3 Hz), 5.76-5.64 (1H, m), 5.04 (1H, d, J=10.2 Hz), 4.93 (1H,dd, J=17.1, 1.5 Hz), 4.74 (2H, d, J=5.9 Hz), 3.97 (1H, s), 3.25-3.15(4H, m), 2.82-2.70 (4H, m), 1.76-1.65 (1H, m), 1.58 (6H, s), 1.13 (6H,d, J=6.0 Hz).

ESI-MS Found: m/z [M+H]F 529.

EXAMPLE 60 Production of2-allyl-6-{[4-(4-cyclopropylpiperazin-1-yl)phenyl]amino}-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

76.6 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-(4-cyclopropylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.85 (1H, t, J=8.0 Hz), 7.76(1H, d, J=8.3 Hz), 7.46 (2H, d, J=8.8 Hz), 7.34 (1H, d, J=7.8 Hz), 6.93(2H, d, J=9.3 Hz), 5.76-5.64 (1H, m), 5.04 (1H, d, J=10.2 Hz), 4.94 (1H,dd, J=17.1, 1.5 Hz), 4.74 (2H, d, J=5.9 Hz), 3.98 (1H, s), 3.20-3.15(4H, m), 2.85-2.79 (4H, m), 1.76-1.65 (1H, m), 1.58 (6H, s), 0.54-0.44(4H; m).

ESI-MS Found: m/z [M+H]+ 527.

EXAMPLE 61 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

46.7 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-[4-(2-methoxyethyl)-1-piperazinyl]aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.85 (1H, t, J=7.8 Hz), 7.75(1H, d, J=7.8 Hz), 7.46 (2H, d, J=8.8 Hz), 7.34 (1H, d, J=7.3 Hz), 6.92(2H, d, J=9.3 Hz), 5.75-5.65 (1H, m), 5.04 (1H, d, J=10.2 Hz), 4.94 (1H,d, J=17.1 Hz), 4.74 (2H, d, J=6.3 Hz), 3.99-3.96 (1H, m), 3.58 (2H, t,J=5.4 Hz), 3.39 (3H, s), 3.25-3.21 (4H, m), 2.73-2.63 (6H, m), 1.59 (6H,s).

ESI-MS Found: m/z [M+H]+ 545.

EXAMPLE 62 Production of2-allyl-6-({4-[4-(2-ethoxyethyl)-1-piperazinyl]phenyl}amino)-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

48.6 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-[4-(2-ethoxyethyl)-1-piperazinyl]aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.85 (1H, t, J=7.8 Hz), 7.75(1H, d, J=7.8 Hz), 7.46 (2H, d, J=8.3 Hz), 7.34 (1H, d, J=7.3 Hz), 6.92(2H, d, J=8.8 Hz), 5.76-5.64 (1H, m), 5.04 (1H, d, J=10.2 Hz), 4.93 (1H,d, J=17.1 Hz), 4.74 (2H, d, J=6.3 Hz), 4.02-3.96 (1H, m), 3.62 (2H, t,J=5.6 Hz), 3.53 (2H, q, J=7.0 Hz), 3.25-3.18 (4H, m), 2.75-2.63 (6H, m),1.58 (6H, s), 1.22 (3H, t, J=7.0 Hz).

ESI-MS Found: m/z [M+H]+ 559

EXAMPLE 63 Production of6-{[4-(4-acetylpiperazin-1-yl)phenyl]amino}-2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

66.4 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-(4-acetyl-1-piperazinyl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 7.87 (1H, t, J=7.8 Hz), 7.74(1H, d, J=8.8 Hz), 7.50 (2H, d, J=8.8 Hz), 7.36 (1H, d, J=8.3 Hz), 6.94(2H, d, J=8.8 Hz), 5.76-5.65 (1H, m), 5.04 (1H, d, J=10.2 Hz), 4.94 (1H,d, J=17.1 Hz), 4.74 (2H, d, J=5.9 Hz), 4.03-3.95 (1H, m), 3.80 (2H, t,J=4.9 Hz), 3.65 (2H, t, J=5.1 Hz), 3.17 (2H, t, J=4.9 Hz), 3.14 (2H, t,J=5.1 Hz), 2.16 (3H, s), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 529.

EXAMPLE 64 Production of2-allyl-6-({4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}amino)-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

40 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,2-[4-(4-aminophenyl)-1-piperazinyl]ethanol was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.86 (1H, t, J=7.8 Hz), 7.75(1H, d, J=7.8 Hz), 7.47 (2H, d, J=8.8 Hz), 7.34 (1H, d, J=8.3 Hz), 6.93(2H, d, J=8.8 Hz), 5.76-5.65 (1H, m), 5.04 (1H, d, J=10.2 Hz), 4.94 (1H,d, J=17.1 Hz), 4.74 (2H, d, J=6.3 Hz), 4.03-3.95 (1H, m), 3.69 (2H, t,J=5.1 Hz), 3.22 (4H, t, J=4.9 Hz), 2.73 (4H, t, J=4.6 Hz), 2.65 (2H, t,J=5.4 Hz), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 531.

EXAMPLE 65 Production of2-allyl-6-({4-[(diethylamino)methyl]phenyl}amino)-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

46 mg of the entitled compound was obtained as a white solid in the samemanner as in Example 53-1 to 53-3, for which, however,4-[(diethylamino)methyl]aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.87 (1.0H, s), 7.89 (1.0H, d, J=7.8 Hz),7.78 (1.0H, d, J=7.8

Hz), 7.55 (2.0H, d, J=8.3 Hz), 7.36 (2.0H, d, J=7.8 Hz), 7.33 (1.0H,brs), 5.71 (1.0H, ddt, J=17.1, 10.2, 6.3 Hz), 5.05 (1.0H, d, J=10.2 Hz),4.94 (1.0H, dd, J=17.1, 1.0 Hz), 4.76 (2.4H, d, J=6.3 Hz), 3.93 (1.0H,brs), 3.57 (2.0H, brs), 2.54 (4.0H, brs), 1.59 (6.0H, s), 1.07 (5.9H, t,J=5.9 Hz).

ESI-MS Found: m/z [M+H]+ 488.

EXAMPLE 66 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-[(1-methyl-1H-pyrazol-3-yl)amino]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

17.5 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 53-1 to 53-3, for which, however,1-methyl-1H-pyrazole-3-amine was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.93 (s, 1H), 7.91 (ddd, 1H, J=7.6, 8.2, 1.0Hz), 7.75 (d, 1H, J=8.2 Hz), 7.37 (d, 1H, J=7.6 Hz), 7.27-7.29 (m, 1H),6.67-6.70 (m, 1H), 5.71 (ddt, 1H, J=17.0, 10.2, 6.3 Hz), 5.04 (d, 1H,J=10.2 Hz), 4.93 (d, 1H, J=17.0 Hz), 4.73 (d, 2H, J=6.3 Hz), 3.94 (brs,1H), 3.85 (s, 3H), 1.59 (s, 6H).

ESI-MS Found: m/z [M+H]+ 407.

EXAMPLE 67 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[5-methyl-6-(4-methyl-1-piperazinyl)-3-pyridinyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

17.7 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,5-methyl-6-(4-methyl-1-piperazinyl)-3-pyridinamine was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.86 (s, 1H), 8.24-8.27 (m, 1H), 7.88 (dd,2H, J=7.6, 8.0 Hz), 7.83-7.85 (m, 2H), 7.73 (d, 1H, J=8.0 Hz), 7.37 (d,1H, J=7.6 Hz), 5.70 (ddt, 1H, J=17.0, 10.0, 6.1 Hz), 5.04 (d, 1H, J=10.0Hz), 4.93 (d, 1H, J=17.0 Hz), 4.75 (d, 2H, J=6.1 Hz), 3.88 (brs, 1H),3.17-3.33 (m, 4H), 2.60-2.83 (m, 2H), 2.39-2.51 (m, 2H), 2.31 (s, 3H),1.59 (s, 9H).

ESI-MS Found: m/z [M+H]+ 516.

EXAMPLE 68 Production of2-allyl-6-anilino-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

7.0 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 53-1 to 53-3, for which, however, aniline wasused in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.87 (1H, s), 7.88 (1H, dd, J=8.0, 7.6 Hz),7.77 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=8.6 Hz), 7.39-7.34 (2H, m), 7.13(1H, dd, J=7.2, 7.2 Hz), 5.70 (1H, ddd, J=17.2, 10.4, 6.4 Hz), 4.03 (1H,s), 1.56 (6H, s).

ESI-MS Found: m/z [M+H]+ 403.

EXAMPLE 69 Production of2-allyl-1-[6-(1-hydroxycyclobutyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of 1-(6-bromo-2-pyrimidinyl)cyclobutanol

In a nitrogen atmosphere at −10° C., 10.8 mL of 2.66 Mn-butyllithium/hexane solution was dropwise added to 16 mL of 0.9 Mn-butylmagnesium chloride/tetrahydrofuran solution, and toluene (60 mL)solution of 9.48 g of 2,6-dibromopyridine was dropwise added thereto at0° C. or lower. The reaction liquid was stirred for 1.5 hours, thencooled in a dry ice/acetone bath, and 5.0 g of cyclobutanone was addedthereto at −50° C. or lower. After stirred for 10 minutes, water and 2 Nhydrochloric acid were added to the reaction liquid, and the organiclayer was separated, washed with aqueous saturated sodiumhydrogencarbonate solution and saturated saline water, and then driedwith anhydrous magnesium sulfate. After concentrated under reducedpressure, the residue was purified through silica gel columnchromatography (hexane/ethyl acetate=20/1 to 4/1) to obtain 5.30 g ofthe entitled compound as a yellow oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.60 (1H, t, J=7.8 Hz), 7.52 (1H, dd, J=7.8,1.0 Hz), 7.40 (1H, dd, J=7.8, 1.0 Hz), 2.53-2.48 (4H, m), 2.12-2.01 (1H,m), 1.91-1.82 (1H, m).

ESI-MS Found: m/z [M+H]+ 228, 230.

2) Production of2-allyl-1-[6-(1-hydroxycyclobutyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

1.44 g of the entitled compound was obtained in the same manner as inExample 53-2, for which, however, the compound obtained in the abovereaction was used in place of 2-(6-bromo-2-pyridinyl)-2-propanol used inExample 53-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.94 (1H, s), 7.95 (1H, t, J=8.0 Hz), 7.77(1H, d, J=7.8 Hz), 7.54 (1H, d, J=7.8 Hz), 5.70 (1H, ddt, J=17.1, 10.2,6.3 Hz), 5.07 (1H, d, J=10.2 Hz), 4.94 (1H, d, J=17.1 Hz), 4.80 (2H, d,J=6.3 Hz), 2.58 (3H, s), 2.56-2.50 (4H, m), 2.15-2.03 (1H, m), 1.97-1.84(1H, m).

ESI-MS Found: m/z [M+H]+ 370.

3) Production of2-allyl-1-[6-(1-hydroxycyclobutyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

80.8 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-3, for which, however, the compoundobtained in the above reaction was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.90 (1H, t, J=7.8 Hz), 7.77(1H, d, J=7.8 Hz), 7.48 (2H, dd, J=12.2, 8.3 Hz), 7.48 (1H, brs), 6.93(2H, d, J=9.3 Hz), 5.70 (1H, tdd, J=5.9, 17.1, 10.0 Hz), 5.04 (1H, dd,J=10.0, 1.2 Hz), 4.94 (1H, dd, J=17.1, 1.0 Hz), 4.73 (2H, d, J=5.9 Hz),4.20 (1H, s), 3.24 (4H, t, J=4.6 Hz), 2.65 (4H, brs), 2.53 (4H, t, J=8.0Hz), 2.41 (3H, s), 2.14-2.06 (1H, m), 1.96-1.84 (1H, m).

ESI-MS Found: m/z [M+H]+ 513.

EXAMPLE 70 Production of2-allyl-6-{[4-(4-cyclopropyl-1-piperazinyl)phenyl]amino}-1-[6-(1-hydroxycyclobutyl)-2-pyridinyl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

65.9 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 69-1 to 69-3, for which, however,4-(4-cyclopropylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 69-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.90 (1H, t, J=8.0 Hz), 7.76(1H, d, J=7.8 Hz), 7.47 (4H, dd, J=15.6, 8.3 Hz), 6.93 (2H, d, J=8.8Hz), 5.70 (1H, ddt, J=17.1, 10.2, 6.3 Hz), 5.04 (1H, d, J=10.2 Hz), 4.94(1H, d, J=17.1 Hz), 4.73 (2H, d, J=6.3 Hz), 4.18 (1H, s), 3.18 (4H, s),2.82 (4H, s), 2.53 (4H, t, J=7.8 Hz), 2.15-2.04 (1H, m), 1.96-1.86 (1H,m), 1.59 (4H, s).

ESI-MS Found: m/z [M+H]+ 539.

EXAMPLE 71 Production of 2-{-4-[4({2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)phenyl]piperidin-1-yl}-N,N-dimethylacetamide

12 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,2-[4-(4-aminophenyl)piperidin-1-yl]-N,N-dimethylacetamide was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.85 (1H, s), 7.88 (1H, dd, J=8.0, 7.6 Hz),7.76 (1H, d, J=8.0 Hz), 7.52 (2H, d, J=8.8 Hz), 7.36 (1H, d, J=7.6 Hz),7.21 (1H, d, J=8.8 Hz), 5.69 (1H, ddt, J=17.2, 10.0, 6.0 Hz), 5.04 (1H,d, J=10.0 Hz), 4.93 (1H, d, J=17.2 Hz), 4.73 (2H, d, J=6.0 Hz), 3.11(3H, s), 3.04-3.08 (1H, m), 2.97 (3H, s), 2.20-2.27 (1H, m), 1.80-1.86(7H, m), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 571.

EXAMPLE 72 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[6-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

39 mg of the entitled compound was obtained as a white solid in the samemanner as in Example 53-1 to 53-3, for which, however,6-(4-methylpiperazin-1-yl)pyridine-3-amine was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CD₃OD) δ: 8.83 (1H, s), 8.31 (1H, br), 7.85 (1H, dd,J=8.0, 7.6 Hz), 7.78 (1H, dd, J=8.0, 2.8 Hz), 7.69 (1H, d, J=8.0 Hz),7.34 (1H, d, J=7.6 Hz), 6.67 (1H, d, J=8.8 Hz), 5.71 (1H, ddt, J=17.2,10.0, 6.0 Hz), 5.04 (1H, d, J=10.0 Hz), 4.93 (1H, d, J=17.2 Hz), 4.73(2H, d, J=6.0 Hz), 3.56 (4H, t, J=4.8 Hz), 2.54 (4H, t, J=4.8 Hz), 2.36(3H, s), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 502.

EXAMPLE 73 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methyl-1,4-diazepan-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

48 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-(4-methyl-perhydro-1H-1,4-diazepin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.83 (1H, dd, J=8.0, 7.6 Hz),7.77 (1H, d, J=8.0 Hz), 7.37 (2H, brs), 7.34 (1H, d, J=7.6 Hz), 6.67(1H, d, J=8.8 Hz), 5.69 (1H, ddt, J=17.2, 10.0, 6.0 Hz), 5.04 (1H, d,J=10.0 Hz), 4.93 (1H, d, J=17.2 Hz), 4.74 (2H, d, J=6.0 Hz), 3.59 (2H,br), 3.51 (2H, br), 2.72 (2H, br), 2.58 (2H, br), 2.39 (3H, s), 2.04(2H, br), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 515.

EXAMPLE 74 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-propionylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

50 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-(4-propionylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 7.86 (1H, dd, J=8.0, 7.6 Hz),7.74 (1H, d, J=8.0 Hz), 7.50 (2H, d, J=8.8 Hz), 7.36 (1H, d, J=7.6 Hz),6.93 (1H, d, J=8.8 Hz), 5.69 (1H, ddt, J=17.2, 10.0, 6.0 Hz), 5.04 (1H,d, J=10.0 Hz), 4.93 (1H, d, J=17.2 Hz), 4.74 (2H, d, J=6.0 Hz), 3.80(2H, br), 3.65 (2H, br), 3.15 (4H, br), 2.41 (2H, q, J=7.6 Hz), 1.59(6H, s), 1.19 (3H, t, J=7.6 Hz).

ESI-MS Found: m/z [M+H]+ 543.

EXAMPLE 75 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-({4-[44(2RS)-3-fluoro-2-hydroxypropyl)piperazin-1-yl]-phenyl}amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

41 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,(±)-1-[4-(4-aminophenyl)piperazin-1-yl]-3-fluoropropan-2-ol was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.86 (1H, dd, J=8.0, 7.6 Hz),7.74 (1H, d, J=8.0 Hz), 7.50 (2H, d, J=8.8 Hz), 7.36 (1H, d, J=7.6 Hz),6.93 (1H, d, J=8.8 Hz), 5.69 (1H, ddt, J=17.2, 10.0, 6.0 Hz), 5.04 (1H,d, J=10.0 Hz), 4.93 (1H, d, J=17.2 Hz), 4.74 (2H, d, J=6.0 Hz),4.33-4.59 (2H, m), 3.99 (1H, br), 3.22 (4H, br), 2.89 (2H, br),2.65-2.84 (3H, m), 2.49-2.53 (1H, m), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 563.

EXAMPLE 76 Production of2-allyl-1-[6-(1-hydroxy-1-methylethy)pyridin-2-yl]-6-({4-[4-(2-hydroxy-2-methylpropyl)piperazin-1-yl]phenyl}amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

49 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,1-[4-(4-aminophenyl)piperazin-1-yl]-2-methylpropan-2-ol was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.86 (1H, dd, J=8.0, 7.6 Hz),7.74 (1H, d, J=8.0 Hz), 7.46 (2H, d, J=8.8 Hz), 7.34 (1H, d, J=7.6 Hz),6.91 (1H, d, J=8.8 Hz), 5.69 (1H, ddt, J=17.2, 10.0, 6.0 Hz), 5.04 (1H,d, J=10.0 Hz), 4.93 (1H, d, J=17.2 Hz), 4.74 (2H, d, J=6.0 Hz), 3.19(4H, br), 2.83 (4H, br), 2.41 (2H, s), 1.59 (6H, s), 1.21 (6H, s).

ESI-MS Found: m/z [M+H]+ 559.

EXAMPLE 77 Production of4-[4-({2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)phenyl]-N,N-dimethylpiperazine-1-carboxamide

33 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-(4-aminophenyl)-N,N-dimethylpiperazine-1-carboxamide was used in placeof 4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.86 (1H, dd, J=8.0, 7.6 Hz),7.75 (1H, d, J=8.0 Hz), 7.48 (2H, d, J=8.8 Hz), 7.34 (1H, d, J=7.6 Hz),6.92 (1H, d, J=8.8 Hz), 5.69 (1H, ddt, J=17.2, 10.0, 6.0 Hz), 5.04 (1H,d, J=10.0 Hz), 4.93 (1H, d, J=17.2 Hz), 4.74 (2H, d, J=6.0 Hz), 3.41(4H, br), 3.17 (4H, br), 2.88 (6H, s), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 558.

EXAMPLE 78 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-[(4-piperazin-1-ylphenyl)amino]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

81 mg of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-({4-[4-(trifluoroacetyl)piperazin-1-yl]phenyl}amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onewas obtained as a yellow solid in the same manner as in Example 53-1 to53-3, for which, however,tert-butyl-4-[(4-trifluoroacetyl)piperazin-1-yl]aniline was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

1.0 mL of aqueous 4 N sodium hydroxide solution was added to 3.0 mL ofmethanol containing 81 mg of the compound obtained in the above, andstirred at room temperature for 1 hour. The reaction liquid wasconcentrated under reduced pressure, water was added thereto, andextracted with a mixed solvent of tetrahydrofuran/ethyl acetate. Thiswas washed with saturated saline water, and dried with anhydrousmagnesium sulfate. Concentrated under reduced pressure, 32.1 mg of theentitled compound was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.85 (1H, s), 7.88 (1H, t, J=7.8 Hz), 7.73(1H, d, J=8.3 Hz), 7.52 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=7.3 Hz), 6.94(2H, d, J=9.3 Hz), 5.71 (1H, ddt, J=17.1, 10.2, 5.9 Hz), 5.05 (1H, d,J=10.7 Hz), 4.94 (1H, d, J=17.1 Hz), 4.74 (2H, d, J=5.9 Hz), 3.93 (1H,brs), 3.39-3.30 (6H, m), 3.21 (1H, brs), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 489.

EXAMPLE 79 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-[{4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl}amino]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

12.1 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 53-1 to 53-3, for which, however,4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.87 (1H, s), 7.90 (1H, t, J=7.8 Hz), 7.76(1H, d, J=7.3 Hz), 7.57 (2H, d, J=8.8 Hz), 7.56 (1H, brs), 7.38 (2H, dd,J=8.5, 2.7 Hz), 6.05 (1H, brs), 5.71 (1H, ddt, J=17.1, 10.2, 5.9 Hz),5.05 (1H, dd, J=10.2, 1.0 Hz), 4.94 (1H, dd, J=17.1, 1.5 Hz), 4.75 (2H,d, J=5.9 Hz), 3.94 (1H, s), 3.26 (2H, brs), 2.81 (2H, brs), 2.67 (2H,brs), 2.51 (3H, s), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 498.

EXAMPLE 80

Production of(±)-2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-({4-[4-((2RS)-2-hydroxypropyl)piperazin-1-yl]phenyl}amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

21 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,1-[4-(4-aminophenyl)piperazin-1-yl]propan-2-ol was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.86 (1H, dd, J=8.0, 7.6 Hz),7.75 (1H, d, J=8.0 Hz), 7.47 (2H, d, J=8.8 Hz), 7.34 (1H, d, J=7.6 Hz),6.92 (1H, d, J=8.8 Hz), 5.70 (1H, ddt, J=17.2, 10.0, 6.0 Hz), 5.04 (1H,d, J=10.0 Hz), 4.93 (1H, d, J=17.2 Hz), 4.74 (2H, d, J=6.0 Hz), 3.93(1H, br), 3.21 (4H, br), 2.87 (2H, brs), 2.62 (2H, brs), 2.36-2.42 (2H,m), 1.59 (6H, s), 1.18 (3H, d, J=6.0 Hz).

ESI-MS Found: m/z [M+H]+ 545.

EXAMPLE 81 Production of2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of 1-(6-bromopyridin-2-yl)-2-methylpropan-2-ol

In a nitrogen atmosphere, 400 mL of tetrahydrofuran containing 31 mL ofdiisopropylamine was cooled in a dry ice/acetone bath, and 82.7 mL of2.66 M n-butyllithium/hexane solution was added thereto, and 50 mL oftetrahydrofuran containing 34.4 g of 6-bromopicoline was dropwise addedthereto at −70° C. or lower. After the addition, 29.4 mL of acetone wasadded thereto at −60° C. or lower. After stirred for 35 minutes, waterwas added to the reaction liquid, and the organic solvent wasconcentrated under reduced pressure. This was extracted with diethylether, washed with saturated saline water, and dried with anhydrousmagnesium sulfate. After concentrated under reduced pressure, theresidue was purified through distillation to obtain 27.60 g of theentitled compound as a colorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.50 (1H, t, J=7.6 Hz), 7.37 (1H, d, J=7.8Hz), 7.12 (1H, d, J=7.8 Hz), 2.91 (2H, s), 1.23 (6H, s).

ESI-MS Found: m/z [M+H]+: 230, 232.

2) Production of2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

20.70 g of the entitled compound was obtained in the same manner as inExample 53-2, for which, however, the compound obtained in the abovereaction was used in place of 2-(6-bromo-2-pyridinyl)-2-propanol used inExample 53-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.93 (1H, s), 7.84 (1H, t, J=7.8 Hz), 7.71(1H, d, J=8.3 Hz), 7.15 (1H, d, J=7.3 Hz), 5.67 (1H, ddt, J=16.8, 10.2,6.3 Hz), 5.05 (1H, dd, J=10.2, 1.0 Hz), 4.93 (1H, dd, J=16.8, 1.2 Hz),4.77 (2H, d, J=6.3 Hz), 2.97 (2H, s), 2.58 (3H, s), 1.25 (6H, s).

ESI-MS Found: m/z [M+H]+ 372.

3) Production of2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

1.06 g of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-3, for which, however, the compoundobtained in the above reaction was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.79 (1H, t, J=7.8 Hz), 7.66(1H, brs), 7.45 (2H, d, J=8.8 Hz), 7.08 (1H, d, J=7.8 Hz), 6.93 (2H, d,J=8.8 Hz), 5.78-5.62 (1H, m), 5.13-4.94 (2H, m), 4.63 (2H, s), 3.23 (4H,t, J=4.6 Hz), 2.98 (2H, s), 2.64 (4H, s), 2.40 (3H, s), 1.24 (6H, s).

ESI-MS Found: m/z [M+H]+ 515.

EXAMPLE 82 Production of2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-{[4-(4-isopropylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

49.1 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 81-1 to 81-3, for which, however,4-(4-isopropylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 81-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.81-7.66 (1H, brm), 7.78 (2H,t, J=7.8 Hz), 7.44 (2H, d, J=8.8 Hz), 7.07 (1H, d, J=7.8 Hz), 6.93 (2H,d, J=8.8 Hz), 5.79-5.61 (1H, m), 5.15-4.91 (2H, m), 4.78-4.48 (2H, m),3.26-3.15 (4H, m), 2.98 (2H, s), 2.74 (1H, septet, J=6.8 Hz), 2.73-2.69(4H, m), 1.24 (6H, s), 1.11 (6H, d, J=6.8 Hz).

ESI-MS Found: m/z [M+H]+ 543.

EXAMPLE 83 Production of2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-{[4-(1-methylpiperidin-4-yl]phenyl}amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

36.8 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 81-1 to 81-3, for which, however,4-(1-methylpiperidin-4-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 81-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.85 (1H, s), 7.89-7.76 (2H, brm), 7.80 (1H,t, J=7.8 Hz), 7.52 (2H, d, J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz), 7.10 (1H,d, J=7.8 Hz), 5.77-5.64 (1H, brm), 5.08 (1H, d, J=9.8 Hz), 5.01 (1H, d,J=17.6 Hz), 4.71-4.58 (2H, brm), 3.05 (2H, d, J=11.2 Hz), 2.99 (2H, s),2.56-2.45 (1H, m), 2.38 (3H, s), 2.21-2.07 (2H, m), 1.95-1.81 (4H, m),1.24 (6H, s).

ESI-MS Found: m/z [M+H]+ 514.

EXAMPLE 84 Production of2-allyl-1-[6-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-2-yl]-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

49.4 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 69-1 to 69-3, for which, however,tetrahydro-4H-pyran-4-one was used in place of cyclobutanone used inExample 69-1; and 3-methyl-4-(4-methylpiperazin-1-yl)aniline was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 69-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 7.92 (1H, t, J=8.0 Hz), 7.84(1H, d, J=8.3 Hz), 7.47 (1H, s), 7.35-7.32 (2H, m), 7.03 (1H, d, J=8.3Hz), 5.70 (1H, ddt, J=17.1, 10.2, 6.3 Hz), 5.04 (1H, dd, J=10.2, 1.2Hz), 4.92 (1H, dd, J=17.1, 1.0 Hz), 4.73 (2H, d, J=6.3 Hz), 4.02-3.93(4H, m), 2.97 (4H, t, J=4.6 Hz), 2.65 (4H, s), 2.41 (3H, s), 2.33 (3H,s), 2.19 (2H, td, J=12.6, 5.4 Hz), 1.62 (2H, d, J=12.2 Hz).

ESI-MS Found: m/z [M+H]+ 557.

EXAMPLE 85 Production of2-allyl-1-[6-(4-hydroxytetrahydro-2H-pyran-4-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

51.1 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 69-1 to 69-3, for which, however,tetrahydro-4H-pyran-4-one was used in place of cyclobutanone used inExample 69-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.91 (1H, t, J=7.8 Hz), 7.79(1H, d, J=7.8 Hz), 7.46 (3H, d, J=8.8 Hz), 7.33 (1H, d, J=7.8 Hz), 6.93(2H, d, J=8.8 Hz), 5.69 (1H, ddt, J=17.1, 10.2, 6.3 Hz), 5.04 (1H, d,J=10.2 Hz), 4.93 (1H, d, J=17.1 Hz), 4.72 (2H, d, J=6.3 Hz), 4.17 (1H,s), 4.03-3.92 (4H, m), 3.26 (4H, s), 2.69 (4H, s), 2.43 (3H, s), 2.19(2H, td, J=12.7, 5.7 Hz), 1.62 (2H, d, J=12.2 Hz).

ESI-MS Found: m/z [M+H]+ 543.

EXAMPLES 86 AND 87 Production of2-allyl-1-{6-[(1R*)-1-hydroxyethyl]pyridin-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,and2-allyl-1-{6-[(1S*)-1-hydroxyethyl]pyridin-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of 1-(6-bromopyridin-2-yl)ethanol

With cooling with ice, 426 mg of sodium borohydride was added to ethanol(50 mL) solution of 4.50 g of 2-acetyl-6-bromopyridine. After stirredfor 1 hour, aqueous saturated ammonium chloride solution was added tothe reaction liquid, extracted with ethyl acetate, washed with saturatedsaline water, and dried with anhydrous magnesium sulfate. Afterconcentrated under reduced pressure, 4.58 g of the entitled compound wasobtained as a colorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.56 (1H, t, J=7.8 Hz), 7.39 (1H, d, J=7.8Hz), 7.29 (1H, d, J=7.8 Hz), 4.88 (1H, q, J=6.7 Hz), 1.51 (3H, d, J=6.3Hz).

ESI-MS Found: m/z [M+H]+ 202, 204.

2) Production of2-allyl-1-{6-[(1R*)-1-hydroxyethyl]pyridin-2-yl}-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,and2-allyl-1-{6-[(1S*)-1-hydroxyethyl]pyridin-2-yl}-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

396 mg of a racemic mixture of the entitled compounds was obtained inthe same manner as in Example 53-2, for which, however, the compoundobtained in the above reaction was used in place of2-(6-bromo-2-pyridinyl)-2-propanol used in Example 53-2.

6.52 g of the above racemate was optically resolved through anoptically-active column (Daicel's CHIRAL PAK AD column, 5 cm×50 cm; 0.1%diethylamine, hexane/ethanol=60/40, flow rate 100 mL/min); and 3.08 g(99.5 ee) of2-allyl-1-{6-[(1R*)-1-hydroxyethyl]pyridin-2-yl}-6-(methylthio)-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-3-onewas obtained as a white solid from the former fraction, and 2.91 g(99.8% ee) of2-allyl-1-{6-[(1S*)-1-hydroxyethyl]pyridin-2-yl}-6-(methylthio)-2,3-dihydro-1H-pyrazolo[3,4-d]pyrimidin-3-onewas as a white solid from the latter fraction. (Since the two were notidentified, one was referred to as 1R* form and the other was as 1S*form for convenience sake.)

(1R* form) of the former fraction:Retention time, 4.9 min (optically-active column; Daicel's CHIRAL PAKAD-H, 0.46 cm×15 cm; 0.1% diethylamine, hexane/ethanol=1/1; flow rate 1mL/min).

¹H-NMR and APCI-MS were the same as those of the racemate.

(1S* form) of the latter fraction:Retention time, 6.7 min (optically-active column; Daicel's CHIRAL PAKAD-H, 0.46 cm×15 cm; 0.1% diethylamine, hexane/ethanol=1/1; flow rate 1mL/min).

¹H-NMR (400 MHz, CDCl₃) δ: 8.94 (1H, s), 7.91 (1H, t, J=7.8 Hz), 7.77(1H, d, J=8.3 Hz), 7.30 (1H, d, J=7.8 Hz), 5.70 (1H, ddt, J=17.2, 10.2,6.3 Hz), 5.06 (1H, dd, J=10.2, 1.5 Hz), 4.96-4.92 (2H, m), 4.80 (2H, dd,J=6.1, 1.2 Hz), 2.58 (3H, s), 1.55 (3H, d, J=6.8 Hz).

ESI-MS Found: m/z [M+H]+ 344.

3) Production of2-allyl-1-{6-[(1R*)-1-hydroxyethyl]pyridin-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,and2-allyl-1-{6-[(1S*)-1-hydroxyethyl]pyridin-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

2-Allyl-1-(6-[(1R*)-1-hydroxyethyl]pyridin-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(compound of Example 86), and2-allyl-1-{6-[(1S*)-1-hydroxyethyl]pyridin-2-yl}-6-([4-(4-methylpiperazin-1-yl)phenyl]amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(compound of Example 87) were obtained both as a yellow solid in anamount of 52.5 mg and 57.9 mg, respectively, in the same manner as inExample 53-3, for which, however, the compound obtained in the abovereaction 2) was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 53-3.

Compound of Example 86:

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.86 (1H, t, J=7.8 Hz), 7.75(1H, d, J=7.8 Hz), 7.46 (3H, d, J=8.8 Hz), 7.24 (2H, d, J=7.8 Hz), 6.93(2H, d, J=8.8 Hz), 5.74-5.66 (1H, m), 5.04 (1H, dd, J=8.8, 1.5 Hz),4.98-4.91 (2H, m), 4.73 (2H, d, J=5.9 Hz), 3.47 (1H, d, J=5.4 Hz), 3.26(4H, s), 2.70 (4H, s), 2.44 (3H, s), 1.55 (3H, d, J=6.8 Hz).

ESI-MS Found: m/z [M+H]+ 487.

Compound of Example 87:

¹H-NMR and ESI-MS were both the same as those of the compound of Example86.

EXAMPLE 88 Production of(±)-2-allyl-1-{6-[(1RS)-1-hydroxyethyl]pyridin-2-yl}-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

83.2 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 86-1 to 86-3, for which, however, a racemicstarting material thereof was used in place of the chiral startingmaterial of2-allyl-1-{6-[(1R*)-1-hydroxyethyl]pyridin-2-yl}-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 86-2, and 3-methyl-4-(4-methylpiperazin-1-yl)aniline wasused in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 86-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 7.87 (1H, t, J=7.8 Hz), 7.80(1H, d, J=7.3 Hz), 7.47 (1H, s), 7.34 (1H, dd, J=8.5, 2.2 Hz), 7.25 (1H,d, J=3.9 Hz), 7.03 (1H, d, J=8.3 Hz), 5.71 (1H, ddt, J=17.1, 10.0, 6.2Hz), 5.04 (1H, dd, J=10.0, 1.2 Hz), 4.94 (1H, d, J=6.3 Hz), 4.94 (1H,dd, J=17.1, 1.2 Hz), 4.74 (2H, d, J=6.2 Hz), 3.46 (1H, d, J=5.4 Hz),2.99 (4H, s), 2.67 (4H, s), 2.44 (3H, s), 2.32 (3H, s), 1.55 (3H, d,J=6.3 Hz).

ESI-MS Found: m/z [M+H]+ 501.

EXAMPLE 89 Production of1-(6-acetylpyridin-2-yl)-2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

33.3 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 29-1 to 29-2, for which, however,2-acetyl-6-bromopyridine was used in place of 2-iodopyridine used inExample 29-1, and 3-methyl-4-(4-methylpiperazin-1-yl)aniline was used inplace of [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used inExample 29-2.

¹H-NMR (400 MHz, DMSO-d₆) δ: 10.25 (1H, brs), 8.89 (1H, s), 8.27-8.22(2H, m), 7.91 (1H, d, J=8.0 Hz), 7.63 (1H, brs), 7.40 (1H, d, J=7.4 Hz),7.00 (1H, d, J=8.6 Hz), 5.69 (1H, ddt, J=16.8, 10.7, 6.5 Hz), 5.01 (1H,d, J=10.7 Hz), 4.92 (1H, d, J=16.8 Hz), 4.75 (2H, d, J=6.5 Hz), 2.82(4H, t, J=4.9 Hz), 2.65 (3H, s), 2.49 (4H, brs), 2.24 (6H, s).

ESI-MS Found: m/z [M+H]+ 499.

EXAMPLE 90 Production of1-(6-acetylpyridin-2-yl)-2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

11.3 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 29-1 to 29-2, for which, however,2-acetyl-6-bromopyridine was used in place of 2-iodopyridine used inExample 29-1, and 4-(4-methylpiperazin-1-yl)aniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.85 (1H, s), 8.15 (1H, dd, J=7.0, 2.2 Hz),8.00-7.94 (2H, m), 7.44 (2H, d, J=8.8 Hz), 7.44 (1H, brs), 6.93 (2H, d,J=8.8 Hz), 5.73-5.63 (1H, m), 5.02 (1H, dd, J=10.3, 1.1 Hz), 4.94-4.87(3H, m), 3.23 (4H, t, J=5.0 Hz), 2.72 (3H, s), 2.63 (4H, brs), 2.39 (3H,s).

ESI-MS Found: m/z [M+H]+ 485.

EXAMPLE 91 Production of2-allyl-1-[6-(2-hydroxyethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of ethyl (6-bromopyridin-2-yl)acetate

412 mg of the entitled compound was obtained as a colorless oilysubstance in the same manner as in Example 81-1, for which, however,diethyl carbonate was used in place of acetone used in Example 81-1.

¹H-NMR (400 MHz, CDCl₃) δ: 7.53 (1H, t, J=7.8 Hz), 7.40 (1H, d, J=7.8Hz), 7.29 (1H, d, J=7.8 Hz), 4.19 (2H, q, J=7.2 Hz), 3.83 (2H, s), 1.27(3H, t, J=7.3 Hz).

ESI-MS Found: m/z [M+H]+ 244, 246.

2) Production of 2-(6-bromopyridin-2-yl)ethanol

In a dry ice/acetone bath, 5.76 mL of 1.01 M diisobutylaluminiumhydride/toluene solution was added to toluene (10 mL) solution of 355 mgof the compound obtained in the above reaction, and stirred for 40minutes. Aqueous saturated ammonium chloride solution was added to thereaction liquid, extracted with ethyl acetate, washed with aqueoussaturated sodium hydrogencarbonate solution and saturated saline water,and dried with anhydrous magnesium sulfate. After concentrated underreduced pressure, the residue was purified through silica gel columnchromatography (hexane/ethyl acetate=3/1 to 1/1) to obtain 123 mg of theentitled compound as a colorless oily substance.

ESI-MS Found: m/z [M+H]+ 202, 204.

3) Production of2-allyl-1-[6-(2-hydroxyethyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

36.6 mg of the entitled compound was obtained as a colorless solid inthe same manner as in Example 53-2, for which, however,2-(6-bromopyridin-2-yl)ethanol obtained in the above reaction was usedin place of 2-(6-bromo-2-pyridinyl)-2-propanol used in Example 53-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.94 (1H, s), 7.84 (1H, t, J=7.6 Hz), 7.66(1H, d, J=7.6 Hz), 7.17 (1H, d, J=7.8 Hz), 5.69-5.64 (1H, m), 5.05 (1H,dd, J=10.4 Hz), 4.94 (1H, dd, J=18.0 Hz), 4.79 (2H, d, J=6.5 Hz), 4.06(2H, t, J=5.5 Hz), 4.06 (2H, t, J=5.5 Hz), 2.58 (3H, s).

ESI-MS Found: m/z [M+H]+ 344

4) Production of2-allyl-1-[6-(2-hydroxyethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

25.9 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-3, for which, however, the compoundobtained in the above reaction was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.78 (1H, t, J=8.0 Hz), 7.50(1H, s), 7.44 (2H, d, J=8.3 Hz), 7.11 (1H, d, J=7.8 Hz), 6.92 (2H, d,J=9.3 Hz), 5.77-5.65 (1H, brm), 5.13-4.93 (2H, brm), 4.67 (2H, brs),4.07 (2H, q, J=5.5 Hz), 3.23 (4H, t, J=4.9 Hz), 3.09 (2H, t, J=5.4 Hz),2.64 (4H, brs), 2.40 (3H, s).

ESI-MS Found: m/z [M+H]+ 487.

EXAMPLE 92 Production of2-{4-[4-({2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)phenyl]piperazin-1-yl}-N,N-dimethylacetamide

60 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-1 to 53-3, for which, however,2-[4-(4-aminophenyl)piperazin-1-yl]-N,N-dimethylacetamide was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.87 (1H, dd, J=8.0, 7.6 Hz),7.74 (1H, d, J=8.0 Hz), 7.46 (2H, d, J=8.8 Hz), 7.34 (1H, d, J=7.6 Hz),6.92 (1H, d, J=8.8 Hz), 5.69 (1H, ddt, J=17.2, 10.0, 6.0 Hz), 5.04 (1H,d, J=10.0 Hz), 4.93 (1H, d, J=17.2 Hz), 4.73 (2H, d, J=6.0 Hz), 3.32(2H, brs), 3.27 (4H, brs), 3.09 (2H, s), 2.98 (3H, s), 2.86 (4H, br),1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 572.

EXAMPLE 93 Production of2-{4-[4-({2-allyl-1-[6-(1-fluoro-1-methylethyl)pyridin-2-yl]-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)phenyl]piperazin-1-yl}-N,N-dimethylacetamide

16 mg of the compound obtained in Example 92 was dissolved in 3 mL ofchloroform, and 0.1 mL of bis(2-methoxyethyl)aminosulfur trifluoride wasadded thereto and stirred at room temperature for 1 hour. Aqueoussaturated sodium hydrogencarbonate solution was added to it andextracted with chloroform. The chloroform layer was washed withsaturated saline water, dried with anhydrous sodium sulfate, and thesolvent was evaporated away under reduced pressure. This was purifiedthrough column chromatography (ethyl acetate/chloroform=3/1) and thensolidified from ethyl acetate/hexane solution to obtain 8 mg of theentitled compound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.80-7.90 (2H, m), 7.46 (2H, d,J=8.8 Hz), 7.45 (1H, overlapped), 6.92 (1H, d, J=8.8 Hz), 5.69 (1H, ddt,J=17.2, 10.0, 6.0 Hz), 5.00 (1H, d, J=10.0 Hz), 4.88 (1H, d, J=17.2 Hz),4.81 (2H, J=6.0 Hz), 3.49 (2H, s), 3.22 (2H, J=4.8 Hz), 3.11 (3H, s),2.98 (3H, s), 2.73 (4H, d, J=4.8 Hz), 1.75 (3H, s), 1.69 (3H, s).

ESI-MS Found: m/z [M+H]+=574.

EXAMPLE 94 Production of2-allyl-1-{6-[(2-hydroxyethyl)(methyl)amino]pyridin-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of 2-[(6-bromopyridin-2-yl)(methyl)amino]ethanol

7.45 g of 2,6-dibromopyridine and 12 mL of N-methylethanol were stirredovernight at 140° C. Water was added to the reaction liquid, extractedwith ethyl acetate, washed with saturated saline water, and dried withanhydrous magnesium sulfate. After concentrated under reduced pressure,the residue was purified through silica gel column chromatography(hexane/ethyl acetate=1/1) to obtain 3.98 g of the entitled compound asa colorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.30 (1H, dd, J=8.3, 7.3 Hz), 6.73 (1H, d,J=7.8 Hz), 6.45 (1H, d, J=8.3 Hz), 3.87 (2H, t, J=4.9 Hz), 3.73 (2H, t,J=4.9 Hz), 3.07 (3H, s).

ESI-MS Found: m/z [M+H]+ 231, 233.

2) Production of2-allyl-1-{6-[(2-hydroxyethyl)(methyl)amino]pyridin-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

40.1 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-2 to 53-3, for which, however, the compoundobtained in the above reaction was used in place of2-(6-bromo-2-pyridyl)-2-propanol used in Example 53-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.58 (1H, t, J=8.0 Hz), 7.44(2H, d, J=8.3 Hz), 6.92 (2H, d, J=9.3 Hz), 6.43 (1H, d, J=8.8 Hz), 5.73(1H, dd, J=17.1, 10.2 Hz), 5.11 (1H, d, J=10.7 Hz), 5.07 (1H, d, J=17.6Hz), 4.52 (2H, brs), 3.93 (4H, brs), 3.24 (4H, brs), 3.12 (3H, s), 2.68(4H, brs), 2.42 (3H, s).

ESI-MS Found: m/z [M+H]+ 516.

EXAMPLE 95 Production of2-allyl-1-[6-(2-hydroxy-1,1,2-trimethylpropyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of ethyl 2-(6-bromopyridin-2-yl)-2-methylpropionate

In a nitrogen atmosphere, 100 mL of tetrahydrofuran containing 14 mL ofdiisopropylamine was cooled in a dry ice-acetone bath, and 38 mL of 2.66M n-butyllithium/hexane solution was added thereto to preparelithium-diisopropylamide. This was dropwise added to 100 mL oftetrahydrofuran containing 4.55 mL of 6-bromopicoline and 6.06 mL ofdiethyl carbonate, at −60° C. or lower. After stirred for 20 minutes,6.23 mL of methyl iodide was added thereto and heated up to roomtemperature. Water was added to the reaction liquid, extracted withdiethyl ether, washed with saturated saline water, and dried withanhydrous magnesium sulfate. After concentrated under reduced pressure,the residue was purified through silica gel column chromatography(hexane/ethyl acetate=100/0 to 8/1) to obtain 10.72 g of the entitledcompound as a colorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.49 (1H, t, J=7.8 Hz), 7.33 (1H, dd, J=7.8,1.0 Hz), 7.22 (1H, dd, J=7.8, 1.0 Hz), 4.16 (2H, q, J=7.0 Hz), 1.59 (6H,s), 1.20 (3H, t, J=7.1 Hz), 0.00 (1H, d, J=3.4 Hz).

ESI-MS Found: m/z [M+H]+ 272, 274.

2) Production of 3-(6-bromopyridin-2-yl)-2,3-dimethylbutan-2-ol

In a nitrogen atmosphere, 13 mL of 2 M methylmagnesium iodide/diethylether solution was added to diethyl ether (20 mL) solution of 2.72 g ofethyl 2-(6-bromopyridin-2-yl)-2-methylpropionate with cooling in an icebath. The reaction liquid was stirred at room temperature for 3 hours,and then water and aqueous 10% phosphoric acid solution were addedthereto, extracted with diethyl ether, washed with aqueous saturatedsodium hydrogencarbonate solution and saturated saline water, and thendried with anhydrous magnesium sulfate. After concentrated under reducedpressure, the residue was purified through silica gel columnchromatography (hexane/ethyl acetate=9/1 to 8/1) to obtain 1.47 g of theentitled compound as a colorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.53 (1H, t, J=7.8 Hz), 7.35 (1H, d, J=7.3Hz), 7.31 (1H, d, J=7.8 Hz), 1.38 (6H, s), 1.09 (6H, s).

ESI-MS Found: m/z [M+H]+ 258, 260.

3) Production of2-allyl-1-[6-(2-hydroxy-1,1,2-trimethylpropyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

74.5 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-2 to 53-3, for which, however, the compoundobtained in the above reaction was used in place of2-(6-bromo-2-pyridyl)-2-propanol used in Example 53-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.81 (1H, t, J=7.9 Hz), 7.81(1H, brs), 7.45 (2H, d, J=8.4 Hz), 7.30 (1H, s), 6.93 (2H, d, J=9.2 Hz),5.71 (1H, s), 5.08 (2H, s), 4.63 (2H, s), 3.24 (4H, s), 2.66 (4H, s),2.41 (3H, s), 1.47 (6H, s), 1.09 (6H, s).

ESI-MS Found: m/z [M+H]+ 543.

EXAMPLE 96

Production ofN-[6-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-a]pyrimidin-1-yl)pyridin-2-yl]acetamide

0.2 mL of acetic anhydride was added to pyridine (2 mL) solution of 50mg of2-allyl-1-(6-aminopyridin-2-yl)-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Example 50, and stirred at 50° C. for 6 hours. After thiswas concentrated under reduced pressure, saturated sodiumhydrogencarbonate solution was added thereto, extracted with chloroform,and the organic layer was washed with saturated saline water and driedwith anhydrous sodium sulfate. The solvent was evaporated away underreduced pressure, and the resulting residue was purified throughpreparative basic thin-layer chromatography (chloroform/methanol=40/1)to obtain 47 mg of the entitled compound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃, 2 drops of CD₃OD) δ: 8.81 (1H, brs), 8.14 (1H,d, J=8.3 Hz), 7.87 (1H, dd, J=8.3, 8.0 Hz), 7.47 (2H, d, J=8.5 Hz), 7.47(1H, d, J=8.0 Hz), 6.91 (2H, d, J=8.5 Hz), 5.67 (1H, ddt, J=17.0, 10.2,6.3 Hz), 5.06 (1H, dd, J=10.2, 1.1 Hz), 4.96 (1H, dd, J=17.0, 1.1 Hz),4.67 (2H, d, J=6.3 Hz), 3.34-3.13 (4H, m), 2.87-2.55 (4H, m), 2.44 (3H,s), 2.24 (3H, s).

ESI-MS Found: m/z [M+H]+ 500.

EXAMPLE 97 Production of2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1-[6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

With cooling with ice, 0.012 mL of triethylamine and 12.4 mg of4-chlorobutyric acid chloride were added to tetrahydrofuran (1 mL)solution of 20 mg of the compound obtained in Example 50,2-allyl-1-(6-aminopyridin-2-yl)-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,and stirred at room temperature for 1 hour. Water was added to thereaction mixture, extracted with chloroform, and the organic layer waswashed with saturated saline water, and dried with anhydrous sodiumsulfate. The solvent was evaporated away under reduced pressure, theresulting residue was dissolved in 1 mL of N,N-dimethylformamide, and 5mg of potassium tert-butoxide was added thereto and stirred at roomtemperature for 30 minutes. Saturated ammonium chloride solution wasadded to the reaction mixture, extracted with ethyl acetate, and theorganic layer was washed with saturated saline water and dried withanhydrous sodium sulfate. The solvent was evaporated away under reducedpressure, and the resulting residue was purified through preparativethin-layer chromatography (chloroform/methanol=10/1) to obtain 5 mg ofthe entitled compound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 8.34 (1H, d, J=8.0 Hz), 7.85(1H, t, J=8.0 Hz), 7.58 (1H, d, J=8.0 Hz), 7.49-7.34 (1H, brm), 7.46(2H, d, J=8.8 Hz), 6.92 (2H, d, J=8.8 Hz), 5.68 (1H, ddt, J=17.1, 10.2,5.9 Hz), 5.04 (1H, dd, J=10.2, 1.0 Hz), 4.94 (1H, dd, J=17.1, 1.0 Hz),4.76 (2H, d, J=5.9 Hz), 4.13-4.04 (2H, m), 3.30-3.20 (4H, m), 2.76-2.61(6H, m), 2.42 (3H, s), 2.21-2.09 (2H, m).

ESI-MS Found: m/z [M+H]+ 526.

EXAMPLE 98 Production of2-allyl-1-[6-(2-hydroxyethoxy)pyridin-2-yl]-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of 2-[(6-bromopyridin-2-yl)oxy]ethanol

8.81 g of ethylene glycol monovinyl ether was added to toluene (100 mL)suspension of 2.4 g of sodium hydride (55% to 72%), and 9.48 g of2,6-dibromopyridine was added thereto and stirred overnight at 110° C.The reaction liquid was left cooled to room temperature, and water wasadded thereto to separate the organic layer. This was washed withsaturated saline water, dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure. 100 mL of methanol and 576 mg ofp-toluenesulfonic acid hydrate were added to the resulting residue, andstirred for 5 hours. After this was concentrated under reduced pressure,aqueous saturated sodium hydrogencarbonate solution was added to it, andextracted with ethyl acetate. This was washed with saturated salinewater, dried with anhydrous magnesium sulfate, concentrated underreduced pressure, and the resulting residue was purified through silicagel column chromatography (hexane/ethyl acetate=9/1 to 2/1) to obtain7.74 g of the entitled compound as a colorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.45 (1H, t, J=7.5 Hz), 7.09 (1H, d, J=7.4Hz), 6.74 (1H, d, J=8.2 Hz), 4.46 (2H, t, J=4.4 Hz), 3.96 (2H, t, J=4.4Hz).

ESI-MS Found: m/z [M+H]+ 218, 220.

2) Production of2-allyl-1-[6-(2-hydroxyethoxy)pyridin-2-yl]-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

870 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 53-2 to 53-3, for which, however, the compoundobtained in the above reaction was used in place of2-(6-bromo-2-pyridyl)-2-propanol used in Example 53-2, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, DMSO-d₆) δ: 10.19 (1H, brs), 8.86 (1H, s), 7.96 (1H, t,J=8.0 Hz), 7.68 (1H, brs), 7.46 (1H, d, J=7.6 Hz), 7.43 (1H, dd, J=8.8,2.9 Hz), 7.00 (1H, d, J=8.6 Hz), 6.82 (1H, d, J=8.2 Hz), 5.70 (1H, ddt,J=18.6, 11.3, 5.5 Hz), 5.05 (1H, d, J=11.3 Hz), 4.93 (1H, d, J=18.6 Hz),4.87 (1H, t, J=5.5 Hz), 4.65 (2H, d, J=4.9 Hz), 4.30 (2H, t, J=5.1 Hz),3.73 (2H, dd, J=10.0, 5.3 Hz), 2.82 (4H, t, J=4.7 Hz), 2.47 (4H, brs),2.25 (6H, s).

ESI-MS Found: m/z [M+H]+ 517.

EXAMPLE 99

Production ofN-{[6-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-2-yl]methyl}-N-methylmethanesulfonamide

1) Production of2-allyl-1-[6-(hydroxymethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

1.36 g of imidazole and 1.81 g of tert-butyl(chloro)dimethylsilane wereadded to N,N-dimethylformamide (30 mL) solution of 3.29 g of thecompound obtained in Example 51-1, and stirred overnight. Water wasadded to the reaction liquid, and extracted with diethyl ether. This waswashed with saturated saline water, and dried with anhydrous magnesiumsulfate.

After concentrated under reduced pressure, the resulting residue waspurified through silica gel column chromatography (hexane/ethylacetate=9/1 to 4/1), and the solvent was evaporated away under reducedpressure. 40 mL of toluene and 3.20 g of m-chloroperbenzoic acid (>65%)were added to the residue, and stirred for 30 minutes. 5.20 mL ofN,N-diisopropylethylamine and 2.29 g of4-(4-methylpiperazin-1-yl)aniline were added to the reaction liquid, andstirred overnight. Aqueous saturated sodium hydrogencarbonate solutionwas added to the reaction liquid, and extracted with ethyl acetate. Thiswas dried with anhydrous magnesium sulfate, the solvent was evaporatedaway, the residue was purified through silica gel column chromatography(chloroform/ethanol=100/1 to 100/3), and the solvent was evaporated awayunder reduced pressure. 50 mL of 4 N hydrochloric acid was added to theresidue, and stirred, and then the solution was made alkaline withaqueous 4 N sodium hydroxide solution. This was extracted with a mixedsolution of chloroform/isopropanol (80/20), dried with anhydrousmagnesium sulfate, the solvent was evaporated away, and the residue wascrystallized in ethyl acetate to obtain 3.78 g of the entitled compoundas a yellow crystal.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.86 (1H, t, J=6.0 Hz), 7.75(1H, d, J=8.2 Hz), 7.46 (2H, d, J=8.6 Hz), 7.40 (1H, brs), 7.22 (1H, d,J=7.6 Hz), 6.92 (2H, d, J=9.0 Hz), 5.71 (1H, ddt, J=16.8, 10.2, 5.9 Hz),5.06 (1H, d, J=10.2 Hz), 4.96 (1H, d, J=16.8 Hz), 4.81 (2H, d, J=5.5Hz), 4.71 (1H, d, J=5.9 Hz), 3.23 (4H, brs), 3.14 (1H, t, J=5.5 Hz),2.64 (4H, brs), 2.40 (3H, s).

ESI-MS Found: m/z [M+H]+ 473.

2) Production of2-allyl-1-{6-[(methylamino)methyl]pyridin-2-yl}-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

4.46 mL of triethylamine and 1.0 mL of methanesulfonyl chloride wereadded to tetrahydrofuran (120 mL) solution of 3.78 g of the compoundobtained in the above 1, and stirred. 20 mL of 2.0 Mmethylamine/tetrahydrofuran solution was added to the reaction liquid,and stirred overnight. Water was added to the reaction liquid, andextracted with ethyl acetate. This was washed with saturated salinewater, dried with anhydrous magnesium sulfate, concentrated underreduced pressure, and the resulting residue was purified through basicsilica gel column chromatography (hexane/ethyl acetate=50/50 to 0/100 tochloroform) to obtain 3.38 g of the entitled compound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.81 (1H, t, J=7.8 Hz), 7.72(1H, d, J=7.8 Hz), 7.46 (2H, d, J=8.8 Hz), 7.25 (1H, d, J=7.3 Hz), 6.92(2H, d, J=9.3 Hz), 5.69 (1H, ddt, J=17.1, 10.2, 6.3 Hz), 5.02 (1H, dd,J=10.2, 1.5 Hz), 4.92 (1H, dd, J=17.1, 1.5 Hz), 4.75 (2H, d, J=6.3 Hz),3.91 (2H, s), 3.21 (4H, t, J=4.9 Hz), 2.62 (4H, t, J=4.9 Hz), 2.51 (3H,s), 2.38 (3H, s).

ESI-MS Found: m/z [M+H]+ 486.

3) Production ofN-{[6-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-2-yl]methyl}-N-methylmethanesulfonamide

1.50 mL of triethylamine and 0.4 mL of methanesulfonyl chloride wereadded to tetrahydrofuran (50 mL) solution of 1.70 g of the compoundobtained in the above 2, and stirred. Water was added to the reactionliquid, and extracted with ethyl acetate. This was washed with saturatedsaline water, dried with anhydrous magnesium sulfate, concentrated underreduced pressure, and the resulting residue was crystallized from 15 mLof ethyl acetate and 10 mL of ethanol to obtain 849 mg of the entitledcompound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.89 (1H, t, J=7.8 Hz), 7.81(1H, d, J=8.3 Hz), 7.48 (1H, d, J=9.3 Hz), 7.47 (1H, brs), 7.41 (2H, d,J=7.3 Hz), 6.93 (2H, d, J=8.8 Hz), 5.68 (1H, ddt, J=17.1, 10.2, 6.3 Hz),5.03 (1H, d, J=10.2 Hz), 4.92 (1H, d, J=18.0 Hz), 4.75 (2H, d, J=6.3Hz), 4.50 (2H, s), 3.38 (4H, brs), 2.95 (3H, s), 2.92 (4H, brs), 2.91(3H, s), 2.58 (3H, s).

ESI-MS Found: m/z [M+H]+ 564.

EXAMPLE 100

Production ofN-{[6-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-2-yl]methyl}-N-methylacetamide

77.5 mg of the entitled compound was obtained as a yellow amorphoussubstance in the same manner as in Example 99-1 to 99-3, for which,however, acetic anhydride was used in place of methanesulfonyl chlorideused in Example 99-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (0.33H, s), 8.82 (0.67H, s), 7.87-7.64(2.00H, m), 7.47 (2.00H, dd, J=8.8, 4.9 Hz), 7.17 (0.67H, d, J=8.3 Hz),7.07 (0.33H, d, J=7.8 Hz), 6.93 (2.00H, dd, J=9.3, 3.4 Hz), 5.73-5.62(1.00H, m), 5.05-4.99 (1.00H, m), 4.92 (1.00H, d, J=17.1 Hz), 4.78(2.00H, d, J=6.3 Hz), 4.70 (1.33H, s), 4.62 (0.67H, s), 3.22 (4.00H, t,J=5.0 Hz), 3.12 (2.00H, s), 3.02 (1.00H, s), 2.63 (4.00H, t, J=5.0 Hz),2.39 (3.00H, s), 2.19 (3.00H, s).

ESI-MS Found: m/z [M+H]+ 528.

EXAMPLE 101

Production ofN-{[6-(2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-2-yl]methyl}-N-methylacetamide

21.9 mg of the entitled compound was obtained as a white amorphoussubstance in the same manner as in Example 99-1 to 99-3, for which,however, 3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 99-1, and aceticanhydride was used in place of methanesulfonyl chloride used in Example99-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (0.33H, s), 8.83 (0.67H, s), 7.88-7.80(2.00H, m), 7.58 (0.33H, s), 7.49 (0.67H, s), 7.34-7.30 (1.00H, m), 7.18(0.67H, t, J=4.1 Hz), 7.09 (0.33H, t, J=4.1 Hz), 7.03 (1.00H, dd, J=8.5,4.6 Hz), 5.73-5.61 (0.99H, m), 5.05-4.99 (1.00H, m), 4.94-4.88 (1.00H,m), 4.81-4.75 (2.00H, m), 4.70 (1.33H, s), 4.62 (0.67H, s), 3.12 (2.00H,s), 3.03 (1.00H, s), 2.97 (4.00H, t, J=5.1 Hz), 2.65 (4.00H, brs), 2.41(3.00H, s), 2.33 (1.00H, s), 2.32 (2.00H, s), 2.19 (3.00H, s).

ESI-MS Found: m/z [M+H]+ 542.

EXAMPLE 102 Production ofN-{[6-(2-allyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-2-yl]methyl}-N-methylmethanesulfonamide

10.4 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 99-1 to 99-3, for which, however,3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 99-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.89 (1H, t, J=7.8 Hz), 7.81(1H, d, J=8.3 Hz), 7.49 (1H, s), 7.48 (1H, d, J=9.3 Hz), 7.41 (1H, d,J=7.3 Hz), 7.02 (1H, d, J=8.8 Hz), 5.68 (1H, ddt, J=17.1, 10.2, 6.3 Hz),5.03 (1H, d, J=10.2 Hz), 4.92 (1H, dd, J=17.1, 1.0 Hz), 4.75 (2H, d,J=6.3 Hz), 4.50 (2H, s), 3.38 (4H, brs), 2.95 (3H, s), 2.92 (4H, brs),2.91 (3H, s), 2.58 (3H, s), 2.32 (3H, s).

ESI-MS Found: m/z [M+H]+ 578.

EXAMPLE 103 Production of2-allyl-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

1) Production of 2-(6-bromopyridin-2-yl)-2-methylpropan-1-ol

In a dry ice/acetone bath, 100 mL of a toluene solution of 1.01 Mdiisobutylaluminium hydride was added to toluene (50 mL) solution of10.72 g of the compound obtained in Example 95-1, heated up to roomtemperature, and stirred for 40 minutes. With cooling with ice, aqueoussaturated ammonium chloride solution was added to the reaction liquid,and, the organic layer was separated. This was washed with aqueoussaturated sodium hydrogencarbonate solution and saturated saline water,dried with anhydrous magnesium sulfate, concentrated under reducedpressure, and the residue was purified through silica gel columnchromatography (ethyl acetate) to obtain 8.74 g of the entitled compoundas a colorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 7.52 (1H, t, J=7.8 Hz), 7.33 (1H, dd, J=7.8,1.0 Hz), 7.27 (1H, d, J=7.8 Hz), 3.74 (2H, s), 1.32 (6H, s).

ESI-MS Found: m/z [M+H]+ 230, 232.

2) Production of2-allyl-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

7.45 g of the entitled compound was obtained in the same manner as inExample 53-2, for which, however, the compound obtained in the abovereaction was used in place of 2-(6-bromo-2-pyridinyl)-2-propanol used inExample 53-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.93 (1H, s), 7.86 (1H, t, J=8.0 Hz), 7.60(1H, d, J=8.8 Hz), 7.31 (1H, d, J=7.8 Hz), 5.67 (1H, ddt, J=17.1, 10.2,6.3 Hz), 5.05 (1H, dd, J=10.2, 1.0 Hz), 4.92 (1H, dd, J=17.1, 1.5 Hz),4.79 (2H, d, J=6.3 Hz), 3.78 (2H, s), 2.58 (3H, s), 1.37 (6H, s).

ESI-MS Found: m/z [M+H]+ 372.

3) Production of2-allyl-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

1.4 g of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-3, for which, however, the compoundobtained in the above reaction was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.81 (1H, t, J=7.8 Hz),7.52-7.41 (3H, m), 7.25 (1H, d, J=9.3 Hz), 6.92 (2H, dd, J=6.8, 2.4 Hz),5.72 (1H, brs), 5.14-4.96 (2H, brm), 4.64 (2H, brs), 3.79 (2H, d, J=6.3Hz), 3.24 (4H, t, J=5.0 Hz), 2.65 (4H, brs), 2.41 (3H, s), 1.38 (6H, s).

ESI-MS Found: m/z [M+H]+ 515.

EXAMPLE 104 Production of2-allyl-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-6-({4-[4(2-methoxyethyl)piperazin-1-yl]phenyl}amino)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

72 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 103-1 to 103-3, for which, however,4-[4-(2-methoxyethyl)piperazin-1-yl]aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 103-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.81 (1H, t, J=7.8 Hz), 7.50(1H, brs), 7.42 (2H, d, J=7.8 Hz), 7.25 (1H, d, J=8.3 Hz), 6.91 (2H, d,J=8.8 Hz), 5.71 (1H, brs), 5.07 (2H, brs), 4.61 (2H, brs), 3.79 (2H, d,J=6.3 Hz), 3.58 (2H, s), 3.38 (3H, s), 3.23 (4H, t, J=4.6 Hz), 2.69 (6H,brs), 1.38 (6H, s).

ESI-MS Found: m/z [M+H]+ 559.

EXAMPLE 105 Production of2-allyl-6-({4-[4-(2-ethoxyethyl)piperazin-1-yl]phenyl}amino)-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

73.3 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 103-1 to 103-3, for which, however,4-[4-(2-ethoxyethyl)piperazin-1-yl]aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 103-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.81 (1H, t, J=8.0 Hz), 7.54(1H, s), 7.43 (2H, d, J=7.8 Hz), 7.25 (2H, d, J=8.3 Hz), 6.91 (2H, d,J=9.3 Hz), 5.70 (1H, brs), 5.08 (2H, brs), 4.61 (2H, brs), 3.79 (2H, s),3.64 (2H, t, J=5.6 Hz), 3.53 (2H, q, J=7.0 Hz), 3.23 (4H, t, J=4.4 Hz),2.79-2.65 (6H, m), 1.38 (6H, s), 1.22 (3H, t, J=7.1 Hz).

ESI-MS Found: m/z [M+H]+ 573.

EXAMPLE 106 Production of2-allyl-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

83.6 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 103-1 to 103-3, for which, however,3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 103-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 7.83 (1H, t, J=7.8 Hz), 7.51(1H, brs), 7.37 (2H, d, J=8.3 Hz), 7.26-7.25 (1H, m), 7.03 (1H, d, J=8.5Hz), 5.78-5.65 (1H, brm), 5.14-4.94 (2H, brm), 4.66 (2H, brs), 3.79 (2H,d, J=6.3 Hz), 3.00 (4H, brs), 2.69 (4H, brs), 2.45 (3H, brs), 2.31 (3H,s), 1.39 (6H, s).

ESI-MS Found: m/z [M+H]+ 529.

EXAMPLE 107 Production of2-allyl-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

49.5 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 103-1 to 103-3, for which, however,4-(1-methylpiperidin-4-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 103-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.86 (1H, s), 7.83 (1H, t, J=8.0 Hz), 7.59(1H, brs), 7.51 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=5.4 Hz), 7.21 (2H, d,J=8.8 Hz), 7.18 (1H, d, J=7.3 Hz), 5.78-3.66 (1H, m), 5.08 d, J=10.2Hz), 5.00 (1H, d, J=15.6 Hz), 4.67 (2H, brs), 3.79 (2H, d, J=6.8 Hz),3.07 (2H, brs), 2.51 (1H, brs), 2.41 (3H, s), 2.36 (1H, s), 2.17 (2H,brs), 1.95-1.82 (4H, brm), 1.39 (6H, s).

ESI-MS Found: m/z [M+H]+ 514.

EXAMPLE 108 Production of2-ethyl-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

27 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 103-1 to 103-3, for which, however, thecompound obtained in Example 28-1 was used in place of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 103-2, and 3-methyl-4-(4-methylpiperazin-1-yl)anilinewas used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example103-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.83 (1H, dd, J=8.0, 7.2 Hz),7.55 (1H, s), 7.38-7.35 (2H), 7.28-7.26 (2H), 7.02 (1H, d, J=8.8 Hz),4.09 (2H, d, J=7.2 Hz), 3.79 (2H, s), 2.96 (4H, m), 2.63 (4H, m), 2.41(3H, s), 2.31 (3H, s), 1.39 (6H, s), 1.21 (3H, t, J=7.2 Hz).

ESI-MS Found: m/z [M+H]+ 517.

EXAMPLE 109 Production of2-ethyl-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

11 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 103-1 to 103-3, for which, however, thecompound obtained in Example 28-1 was used in place of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 103-2, and[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 103-3.

¹H-NMR (400 MHz, CD₃OD) δ: 8.83 (1H, s), 8.03 (1H, dd, J=8.0, 8.0 Hz),7.91 (1H, s), 7.88 (1H, d, J=8.0 Hz), 7.55 (1H, d, J=8.0 Hz), 7.46 (1H,d, J=8.0 Hz), 7.16 (1H, d, J=8.0 Hz), 4.76 (2H, s), 4.26 (2H, q, J=7.2Hz), 3.00 (4H, m), 2.67 (4H, m), 2.41 (3H, s), 1.38 (6H, s), 1.12 (3H,t, J=7.2 Hz).

ESI-MS Found: m/z [M+H]+ 533.

EXAMPLE 110 Production of2-ethyl-1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

21 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 103-1 to 103-3, for which, however, thecompound obtained in Example 28-1 was used in place of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 103-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.82 (1H, dd, J=8.0, 8.0 Hz),7.52 (1H), 7.43 (2H, d, J=9.2 Hz), 7.26-7.25 (1H), 6.92 (1H, d, J=9.2Hz), 4.05 (1H, q, J=7.6 Hz), 3.80 (2H, s), 3.23 (4H, m), 2.64 (4H, m),2.94 (3H, s), 1.39 (6H, s), 1.11 (3H, t, J=7.6 Hz).

ESI-MS Found: m/z [M+H]+ 503.

EXAMPLE 111 Production of2-benzyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl]phenyl}dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of2-benzyl-6-(methylthio)-1-phenyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

33 mg of potassium hydroxide and 0.092 mL of benzyl bromide were addedin that order to ethanol (10 mL) solution of 100 mg of the compoundobtained in Production Example 4, and heated under reflux for 23 hours.The reaction liquid was concentrated under reduced pressure, and theresidue was separated and purified through silica gel columnchromatography (hexane/ethyl acetate=60/40) to obtain 74 mg of theentitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.53-7.20 (10H, m), 2.48 (3H,s).

ESI-MS Found: m/z [M+H]+ 349.

2) Production of2-benzyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-phenyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

46 mg of m-chloroperbenzoic acid was added to chloroform (2 mL) solutionof 74 mg of the compound obtained in the above 1, and stirred at roomtemperature for 20 minutes. The reaction liquid was washed with aqueoussaturated sodium hydrogencarbonate solution, and dried with anhydroussodium sulfate. The solvent was evaporated away under reduced pressureto obtain crude2-benzyl-6-(methylsulfinyl)-1-phenyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneas a white solid.

25 mg of 4-[3-methyl-4-(4-methylpiperazin-1-yl)]aniline and 0.05 mL ofN,N-diisopropylethylamine were added in that order to toluene (5 mL)solution of 25 mg of the above compound, and stirred at 120° C. for 15hours. The solvent was evaporated away under reduced pressure, water wasadded thereto, extracted with ethyl acetate, and dried with anhydroussodium sulfate. The solvent was evaporated away under reduced pressure,and the residue was separated and purified through basic silica gelcolumn chromatography (ethyl acetate) to obtain 24.7 mg of the entitledcompound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 6.91-7.53 (13H, m), 4.97 (2H,s), 2.91 (4H, s), 2.55-2.69 (4H, bs), 2.38 (3H, s), 2.25 (3H, s).

ESI-MS Found: m/z [M+H]+ 506.

EXAMPLE 112 Production of6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-phenyl-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

65.3 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 111-1 to 111-2, for which, however,3-bromo-1-propyne was used in place of benzyl bromide used in Example111-1, and [5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol was usedin place of 3-methyl-4-(4-methylpiperazin-1-yl)aniline used in Example111-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.62-7.18 (9H, m), 4.75 (2H,s), 4.51 (2H, d, J=2.1 Hz), 3.02-2.99 (4H, m), 2.74-2.63 (4H, m), 2.38(3H, s), 2.16 (1H, d, J=2.1 Hz).

ESI-MS Found: m/z [M+H]+ 470.

EXAMPLE 113 Production of1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

1) Production of1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-(methylthio)-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

440 mg of ammonium formate and 230 mg of[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride wereadded to tetrahydrofuran (13.6 mL) solution of 500 mg of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneproduced in Example 53, and stirred at 90° C. for 3 hours. The reactionliquid was cooled to room temperature, distilled water was addedthereof, and extracted with a mixed solution of chloroform/isopropanol(80/20). This was dried with anhydrous sodium sulfate, and the solventwas evaporated away under reduced pressure to obtain 770 mg of a blackamorphous substance. 61.0 mg of sodium hydride was added toN,N-dimethylformamide (14.0 mL) solution of the resulting compound, andstirred for 30 minutes. 0.316 mL of propargyl bromide was added to thereaction solution, and stirred for 3.5 hours. Aqueous saturated sodiumhydrogencarbonate solution and saturated saline water were added to thereaction liquid, and extracted with a mixed solution ofchloroform/isopropanol (80/20). This was dried with anhydrous sodiumsulfate, and the solvent was evaporated away under reduced pressure toobtain a black amorphous substance. The resulting amorphous substancewas purified through silica gel column chromatography (hexane/ethylacetate) to obtain 254 mg of the entitled compound as a white compound.

¹H-NMR (400 MHz, CDCl₃) δ: 8.94 (1H, s), 7.94 (2H, d, J=3.6 Hz), 7.43(1H, t, J=3.6 Hz), 4.97 (2H, d, J=2.4 Hz), 2.62 (3H, s), 2.16 (1H, t,J=2.4 Hz), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 357.

2) Production of1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

7.3 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-3, for which, however, the compoundobtained in the above reaction was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.92 (1H, d, J=8.0 Hz), 7.87(1H, dd, J=8.0, 8.0 Hz), 7.47 (2H, d, J=7.6 Hz), 7.35 (1H, d, J=8.0 Hz),6.94 (2H, d, J=7.6 Hz), 4.89 (2H, d, J=2.0 Hz), 3.23 (4H, m), 2.63 (4H,m), 2.39 (3H, s), 2.13 (1H, t, J=2.0 Hz), 1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 499.

EXAMPLE 114 Production of6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-propynyl)-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

17.0 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Example 29-1 was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1, and 3-methyl-4-(4-methylpiperazin-1-yl)anilinewas used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example113-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 8.49 (1H, d, J=4.0 Hz), 8.19(1H, d, J=4.0 Hz), 7.87 (1H, dd, J=8.0, 8.0 Hz), 7.54 (1H, d, J=2.0 Hz),7.32 (1H, dd, J=8.8, 2.0 Hz), 7.25 (1H, dd, J=8.0, 4.0 Hz), 7.04 (1H, d,J=8.8 Hz), 4.99 (2H, d, J=1.6 Hz), 2.96 (4H, m), 2.61 (4H, m), 2.39 (3H,s), 2.34 (3H, s), 2.07 (1H, d, J=1.6 Hz).

ESI-MS Found: m/z [M+H]+ 455.

EXAMPLE 115 Production of6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-propynyl)-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

20 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Example 29-1 was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 8.07 (1H, d, J=7.6 Hz), 7.85,(1H, dd, J=8.4, 7.6 Hz), 7.47 (2H, d, J=9.2 Hz), 7.22 (1H, dd, J=7.6,4.8 Hz), 6.96 (1H, d, J=9.2 Hz), 4.99 (2H, d, J=1.6 Hz), 3.23 (4H, m),2.62 (4H, m), 2.39 (3H, s), 2.07 (1H, d, J=1.6 Hz).

ESI-MS Found: m/z [M+H]+ 441.

EXAMPLE 116 Production of6-{[3-hydroxymethyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-propynyl)-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

10 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Example 29-1 was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1, and[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.

¹H-NMR (400 MHz, CD₃OD) δ: 8.84 (1H, s), 8.50 (1H, d, J=9.0 Hz), 8.16(1H, d, J=8.4 Hz), 8.08 (1H, dd; J=8.8, 8.4 Hz), 7.94 (1H, d, J=2.0 Hz),7.53 (1H, d, J=8.4, 2.0 Hz), 7.38 (1H, dd, J=8.8, 3.6 Hz), 7.18 (2H, d,J=8.4 Hz), 4.94 (2H, d, J=2.0 Hz), 4.78 (2H, s), 3.01 (4H, m), 2.68 (4H,m), 2.62 (1H, d, J=2.0 Hz), 2.41 (3H, s).

ESI-MS Found: m/z [M+H]+ 470.

EXAMPLE 117 Production of1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

76 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Example 81-2 was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.98 (1H, dd, J=8.0, 8.0 Hz),7.45 (2H, m), 7.85 (1H, d, J=8.0 Hz), 6.94 (1H, d, 8.8 Hz), 4.80 (1H,s), 3.22 (4H, m), 2.37 (2H, s), 2.33 (1H, s), 1.24 (6H, s).

ESI-MS Found: m/z [M+H]+ 513.

EXAMPLE 118 Production of6-{[4-(4-acetylpiperazin-1-yl)phenyl]amino}-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

7.4 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,4(4-acetylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 7.92-7.86 (2H, m), 7.51 (2H, d,J=9.2 Hz), 7.36 (1H, d, J=6.8 Hz), 6.95 (2H, d, J=9.2 Hz), 4.90 (2H, s),3.81-3.65 (4H), 3.66 (4H, m), 3.17 (4H, m), 2.17 (3H, s), 2.13 (1H, s),1.59 (6H, s).

ESI-MS Found: m/z [M+H]+ 527.

EXAMPLE 119 Production of2-{4-[4-({1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-3-oxo-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)phenyl]piperazin-1-yl}-N,N-dimethylacetamide

14 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-[4-(4-aminophenyl)piperazin-1-yl]-N,N-dimethylacetamide was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.91 (1H, dd, J=8.0, 8.0 Hz),7.86 (1H, d, J=8.0 Hz), 7.47 (2H, d, J=9.2 Hz), 7.35 (1H, d, J=8.0 H),6.94 (2H, d, J=9.2 Hz), 4.89 (2H, d, J=2.4 Hz), 3.27 (4H, m), 3.23 (3H,s), 2.98 (3H, s), 2.74 (4H, m), 2.13 (1H, t, J=2.4 Hz), 1.58 (6H, s).

ESI-MS Found: m/z [M+H]+ 570.

EXAMPLE 120 Production of1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-({4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}amino)-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

14 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,4-[4-(2-methoxyethyl)piperazin-1-yl]aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.91 (1H, dd, J=8.0, 8.0 Hz),7.85 (1H, d, J=8.0 Hz), 7.47 (1H, d, J=8.8 Hz), 7.34 (1H, d, J=8.0 Hz),6.94 (2H, d, J=8.8 Hz), 4.89 (2H, d, J=2.8 Hz), 3.82-3.60 (4H), 3.27(4H, m), 2.74 (4H, m), 2.13 (1H, t, J=2.8 Hz), 1.58 (6H, s).

ESI-MS Found: m/z [M+H]+ 543.

EXAMPLE 121 Production of6-({4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}amino)-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

14 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,4-[4-(2-ethoxyethyl)piperazin-1-yl]aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (1H, s), 7.91 (1H, dd, J=8.0, 8.0 Hz),7.85 (1H, d, J=8.0 Hz), 7.47 (2H, d, J=9.2 Hz), 6.94 (2H, d, J=9.2 Hz),4.89 (2H, d, J=2.4 Hz), 3.82-3.64 (4H), 3.25 (4H, m), 2.75 (4H, m), 2.13(1H, t, J=2.4 Hz), 1.58 (6H, s), 1.23 (3H, t, J=6.8 Hz).

ESI-MS Found: m/z [M+H]+ 557.

EXAMPLE 122 Production of6-({4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}amino)-1-(6-methylpyridin-2-yl)-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

45.3 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onewas used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1, and 4-[4-(2-methoxyethyl)piperazin-1-yl]anilinewas used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example113-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.83 (1H, d, J=8.0 Hz), 7.73(1H, t, J=8.0 Hz), 7.48 (2H, d, J=9.0 Hz), 7.07 (1H, d, J=8.0 Hz), 6.93(2H, d, J=9.0 Hz), 4.98 (2H, d, J=2.3 Hz), 3.62-3.55 (2H, brm), 3.39(3H, s), 3.28-3.20 (4H, brm), 2.76-2.64 (6H, brm), 2.57 (3H, s), 2.07(1H, t, J=2.3 Hz).

ESI-MS Found: m/z [M+H]+ 499.

EXAMPLE 123 Production of6-({4-[4-(2-ethoxyethyl)piperzin-1-yl]phenyl}amino)-1-(6-methylpyridin-2-yl)-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

31.8 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onewas used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1, and 4-[4-(2-ethoxyethyl)piperazin-1-yl]anilinewas used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example113-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.83 (1H, d, J=8.0 Hz), 7.73(1H, t, J=8.0 Hz), 7.47 (2H, d, J=8.8 Hz), 7.07 (1H, d, J=8.0 Hz), 6.93(2H, d, J=8.8 Hz), 4.98 (2H, d, J=2.0 Hz), 3.63 (2H, t, J=5.7 Hz), 3.53(2H, q, J=7.0 Hz), 3.27-3.19 (4H, brm), 2.78-2.64 (6H, brm), 2.57 (3H,s), 2.07 (1H, t, J=2.0 Hz), 1.23 (3H, t, J=7.0 Hz).

ESI-MS Found: m/z [M+H]+ 513.

EXAMPLE 124

Production ofN,N-dimethyl-2-[4-(4-{[1-(6-methylpyridin-2-yl)-3-oxo-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-6-yl]amino}phenyl)piperazin-1-yl]acetamide

34.3 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onewas used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1, and2-[4-(4-aminophenyl)piperazin-1-yl]-N,N-dimethylacetamide was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.83 (1H, d, J=8.0 Hz), 7.74(1H, t, J=8.0 Hz), 7.48 (2H, d, J=9.0 Hz), 7.07 (1H, d, J=8.0 Hz), 6.93(2H, d, J=9.0 Hz), 4.98 (2H, d, J=2.3 Hz), 3.28 (2H, s), 3.27-3.21 (4H,brm), 3.11 (3H, s), 2.98 (3H, s), 2.82-2.71 (4H, brm), 2.57 (3H, s),2.07 (1H, t, J=2.3 Hz).

ESI-MS Found: m/z [M+H]+ 526.

EXAMPLE 125 Production of6-{[4-(4-acetylpiperazin-1-yl)phenyl]amino}-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

23 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Example 81-2 was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1, and 4-(4-acetylpiperazin-1-yl)aniline was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 7.80 (1H, dd, J=8.0, 8.0 Hz),7.75 (1H, d, J=8.0 Hz), 7.49 (2H, d, J=8.4 Hz), 7.08 (1H, d, J=8.0 Hz),6.94 (2H, d, J=8.4 Hz), 4.80 (2H, s), 3.80 (2H, m), 3.65 (2H, m), 3.17(4H, m), 2.98 (2H, s), 2.15 (3H, s), 2.12 (1H, s), 1.26 (6H, s).

ESI-MS Found: m/z [M+H]+ 541.

EXAMPLE 126 Production of2-{4-[4-({1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-3-oxo-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-6-yl}amino)phenyl]piperazin-1-yl}-N,N-dimethylacetamide

27 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Example 81-2 was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1, and2-[4-(4-aminophenyl)piperazin-1-yl]-N,N-dimethylacetamide was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.80 (1H, dd, J=8.0, 7.2 Hz),7.80-7.60 (1H), 7.45 (2H, d, J=9.6 Hz), 7.07 (2H, d, J=7.2 Hz), 6.93(2H, d, J=9.6 Hz), 4.83 (1H, s), 3.26-3.23 (6H), 3.11 (3H, s), 2.98 (3H,s), 2.73 (4H, m), 2.11 (1H, s), 1.24 (6H, s).

ESI-MS Found: m/z [M+H]+ 541.

EXAMPLE 127 Production of1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-({4-[4-(2-methoxyethyl)piperazin-1-yl]phenyl}amino)-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

31 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Example 81-2 was used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1, and 4-[4-(2-methoxyethyl)piperazin-1-yl]anilinewas used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example113-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.79 (1H, d, J=7.6 Hz), 7.79(1H, dd, J=7.6, 7.6 Hz), 7.45 (2H, d, J=8.8 Hz), 7.07 (1H, d, J=7.6 Hz),6.93 (2H, d, J=8.8 Hz), 5.0-4.8 (2H, m), 3.57 (2H, d, J=5.6 Hz), 3.39(3H, s), 3.23 (4H, m), 2.64-2.69 (6 Hr, m), 2.11 (1H, s), 1.24 (6H, s).

ESI-MS Found: m/z [M+H]+ 557.

EXAMPLE 128 Production of6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(6-methylpyridin-2-yl)-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

51.4 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onewas used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 7.83 (1H, d, J=7.8 Hz), 7.74(1H, t, J=7.8 Hz), 7.62-7.43 (1H, brm), 7.48 (2H, d, J=8.8 Hz), 7.07(1H, d, J=7.8 Hz), 6.94 (2H, d, J=8.8 Hz), 4.98 (2H, d, J=2.4 Hz),3.30-3.19 (4H, m), 2.71-2.61 (4H, m), 2.57 (3H, s), 2.40 (3H, s), 2.07(1H, t, J=2.4 Hz).

ESI-MS Found: m/z [M+H]+ 455.

EXAMPLE 129

Production of[6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(6-methylpyridin-2-yl)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-2-yl]acetonitrile

21 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 113-1 to 113-2, for which, however,2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onewas used in place of2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 113-1, and iodoacetonitrile was used in place of3-bromo-1-propyne used in Example 113-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.79 (1H), 7.87 (1H, d, J=8.0 Hz), 7.45 (1H,dd, J=8.0, 8.0 Hz), 7.70 (2H, d, J=8.8 Hz), 7.60 (1H, s), 7.10 (1H, d,J=8.0 Hz), 6.98 (2H, d, J=8.0 Hz), 5.23 (2H, s), 3.22 (4H, m), 2.72 (3H,s), 2.63 (4H, m), 2.39 (3H, s).

ESI-MS Found: m/z [M+H]+ 456.

EXAMPLE 130 Production of2-(2-methoxyphenyl)-1-methyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onemonotrifluoroacetate 1) Production of1-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

2.3 g of the entitled compound was obtained as a pale yellow solid inthe same manner as in Production Example 4, for which, however,methylhydrazine was used in place of phenylhydrazine used in ProductionExample 4.

2) Production of2-(2-methoxyphenyl)-1-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

280 mg of o-methoxyphenylboronic acid, 320 mg of copper(II) acetate and0.15 mL of pyridine were added to a chloroform/N,N-dimethylformamide(1/1) solution of 90 mg of1-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,and stirred at room temperature. Aqueous 28% ammonia solution andsaturated sodium hydrogencarbonate solution were added to the reactionliquid, and extracted with chloroform. The crude product was purifiedthrough a silica gel column (hexane/ethyl acetate) to obtain 68 mg of2-(2-methoxyphenyl)-1-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.

¹H-NMR (400 MHz, CDCl₃) δ: 8.88 (1H, s), 7.52-7.47 (1H, m), 7.38 (1H,dd, J=7.6, 1.7 Hz), 7.11 (1H, dd, J=7.6, 1.0 Hz), 7.07 (1H, dd, J=8.3,1.0 Hz), 3.81 (3H, s), 3.33 (3H, s), 2.63 (3H, s).

3) Production of2-(2-methoxyphenyl)-1-methyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onemonotrifluoroacetate

At 0° C., 68 mg of m-chloroperbenzoic acid was added to a chloroformsolution of 91 mg of2-(2-methoxyphenyl)-1-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,and stirred for 1 hour. Aqueous saturated sodium hydrogencarbonatesolution was added thereto, and extracted with chloroform to obtaincrude 2-(2-methoxyphenyl)-1-methyl-6-(methylsulfinyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.

58 mg of 3-methyl-4-(4-methylpiperazin-1-yl)aniline and 0.1 mL ofN,N-diisopropylethylamine were added to a toluene solution of 30 mg ofthe compound obtained in the above, and stirred at 130° C. for 12 hours.The solvent was evaporated away, the residue was purified throughreversed-phase chromatography to obtain 56 mg of yellow amorphous2-(2-methoxyphenyl)-1-methyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onemonotrifluoroacetate.

¹H-NMR (400 MHz, CD₃OD) δ: 8.74 (1H, s), 7.62-7.57 (2H, m), 7.55-7.52(1H, m), 7.46 (1H, dd, J=7.8, 1.6 Hz), 7.24 (1H, d, J=8.4 Hz), 7.18-7.11(2H, m), 3.83 (3H, s), 3.62-3.55 (2H, m), 3.37-3.24 (7H, m), 3.13-3.03(2H, m), 2.97 (3H, s), 2.35 (3H, s).

ESI-MS Found: m/z [M+H]+ 460.

EXAMPLE 131 Production of2-(2-chlorophenyl)-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of2-(2-chlorophenyl)-1-methyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

2 mL of methyl iodide and 2.2 g of sodium carbonate were added in thatorder to acetonitrile (50 mL) solution of 2 g of the compound obtainedin Production Example 2, and heated under reflux for 1 hour. Thereaction liquid was concentrated under reduced pressure, and the residuewas separated and purified through silica gel column chromatography(hexane/ethyl acetate=60/40) to obtain 1.14 g of the entitled compoundas a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.91 (1H, s), 7.42-7.63 (4H, m), 3.34 (3H,s), 2.64 (3H, s).

ESI-MS Found: m/z [M+H]+ 307.

2) Production of2-(2-chlorophenyl)-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

916 mg of m-chloroperbenzoic acid was added to chloroform (10 mL)solution of 1.14 g of the compound obtained in the above 1, and stirredat room temperature for 20 minutes. The reaction liquid was washed withaqueous saturated sodium hydrogencarbonate solution, and dried withanhydrous sodium sulfate. The solvent was evaporated away under reducedpressure to obtain crude2-(2-chlorophenyl)-1-methyl-6-(methylsulfinyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneas a white solid.

200 mg of 4-[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)]aniline and0.2 mL of N,N-diisopropylethylamine were added in that order to toluene(20 mL) solution of 200 mg of the above compound, and stirred at 120° C.for 15 hours. The solvent was evaporated away under reduced pressure,water was added to the residue, extracted with ethyl acetate, and driedwith anhydrous sodium sulfate. The solvent was evaporated away underreduced pressure, and the residue was separated and purified throughbasic silica gel column chromatography (ethyl acetate) to obtain 161 mgof the entitled compound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 7.43-7.58 (7H, m), 4.82 (2H,s), 3.28 (3H, s), 2.52-3.04 (8H, m), 2.38 (3H, s).

ESI-MS Found: m/z [M+H]+ 480.

EXAMPLE 132 Production of2-(2-chlorophenyl)-1-methyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

10 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 131-1 to 131-2, for which, however,3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example131-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.37-7.61 (6H, m), 7.06 (1H, d,J=8.3 Hz), 3.27 (3H, s), 2.95 (4H, t, J=4.1 Hz), 2.53-2.75 (4H, m), 2.38(3H, s), 2.23 (3H, s).

ESI-MS Found: m/z [M+H]+ 464.

EXAMPLE 133 Production of2-(2-chlorophenyl)-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of2-(2-chlorophenyl)-6-(methylthio)-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

15 mg of the entitled compound was obtained as a white solid in the samemanner as in Example 1-1, for which, however, 3-thienylboronic acid wasused in place of [3-(methoxycarbonyl)]phenylboronic acid used in Example1-1.

2) Production of2-(2-chlorophenyl)-6-([3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino)-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

10.1 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-2 to 1-3, for which, however, the compoundobtained in the above reaction was used in place of methyl3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoateused in Example 1-2, and 3-methyl-4-(4-methylpiperazin-1-yl)aniline wasused in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.88 (1H, s), 7.20-7.53 (9H, m), 7.01 (1H, d,J=7.6 Hz), 2.96 (4H, m), 2.64 (4H, brs), 2.39 (3H, s), 2.31 (3H, s).

ESI-MS Found: m/z [M+H]+ 533.

EXAMPLE 134 Production of2-(2-chlorophenyl)-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of2-(2-chlorophenyl)-6-(methylthio)-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

736 mg of (2-pyridyl)tributyltin, 362 mg of copper(II) acetate and 1.1mL of pyridine were added in that order to N,N-dimethylformamide (50 mL)solution of 292 mg of the compound obtained in Production Example 2, andstirred at room temperature for 48 hours. Aqueous 28% ammonia was addedto the reaction liquid, extracted with ethyl acetate, and dried withanhydrous sodium sulfate. The solvent was concentrated under reducedpressure, and the residue was separated and purified through silica gelcolumn chromatography (hexane/ethyl acetate=80/20) to obtain 65.2 mg ofthe entitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 9.02 (1H, s), 8.30 (1H, d, J=5.2 Hz),7.76-7.84 (2H, m), 7.58-7.65 (1H, m), 7.42-7.47 (1H, m), 7.26-7.33 (2H,m), 7.12-7.16 (1H, m), 2.62 (3H, s).

ESI-MS Found: m/z [M+H]+ 370.

2) Production of2-(2-chlorophenyl)-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

44.2 mg of m-chloroperbenzoic acid was added to chloroform (5 mL)solution of 65.2 mg of the compound obtained in the above 1, and stirredat room temperature for 30 minutes. The reaction liquid was washed withaqueous saturated sodium hydrogencarbonate solution, and dried withanhydrous sodium sulfate. The solvent was evaporated away under reducedpressure to obtain crude2-(2-chlorophenyl)-6-(methylsulfinyl)-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneas a white solid.

60 mg of 4-[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)]aniline and 0.1mL of N,N-diisopropylethylamine were added in that order to toluene (5mL) solution of the above compound, and stirred at 120° C. for 15 hours.The solvent was evaporated away under reduced pressure, then water wasadded to it, extracted with ethyl acetate, and dried with anhydroussodium sulfate. The solvent was evaporated away under reduced pressure,and the residue was separated and purified through basic silica gelcolumn chromatography (ethyl acetate) to obtain 24.7 mg of the entitledcompound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.93 (1H, s), 8.37 (1H, d, J=3.9 Hz), 7.79(1H, t, J=6.8 Hz), 7.71 (1H, d, J=7.8 Hz), 7.68-7.57 (1H, m), 7.57 (1H,dd, J=6.1, 3.7 Hz), 7.44 (1H, dd, J=6.1, 3.7 Hz), 7.41-7.36 (1H, m),7.30-7.24 (2H, m), 7.21 (1H, d, J=8.8 Hz), 7.15 (1H, dd, J=6.8, 5.4 Hz),4.79 (2H, s), 3.03 (4H, t, J=4.6 Hz), 2.77-2.53 (4H, m), 2.39 (3H, s).

ESI-MS Found: m/z [M+H]+ 543.

EXAMPLE 135 Production of2-benzyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of2-benzyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

2.9 g of the entitled compound was obtained as a white solid in the samemanner as in Production Example 1-2, for which, however, benzylhydrazinewas used in place of tert-butyl 1-allylhydrazinecarboxylate used inProduction Example 1-2.

¹H-NMR (400 MHz, DMSO-d₆) δ: 12.8 (1H, s), 8.63 (1H, s), 7.20-7.33 (5H,m), 4.94 (2H, s), 2.49 (3H, s).

ESI-MS Found: m/z [M+H]+ 273.

2) Production of2-benzyl-6-(methylthio)-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

300 mg of (2-pyridyl)tributyltin, 267 mg of copper(II) acetate and 1.0mL of pyridine were added in that order to N,N-dimethylformamide (10 mL)solution of 200 mg of the compound obtained in the above 1, and stirredat room temperature for 48 hours. Aqueous 28% ammonia was added to thereaction liquid, extracted with ethyl acetate, and dried with anhydroussodium sulfate. The solvent was concentrated under reduced pressure, andthe residue was separated and purified through silica gel columnchromatography (hexane/ethyl acetate=80/20) to obtain 111.2 mg of theentitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.94 (1H, s), 8.56 (1H, d, J=4.9 Hz), 7.83(1H, t, J=8.5 Hz), 7.66 (1H, d, J=8.5 Hz), 7.12-7.31 (4H, m), 6.92 (1H,d, J=6.8 Hz), 5.44 (2H, s), 2.53 (3H, s).

ESI-MS Found: m/z [M+H]+ 350.

3) Production of2-benzyl-6-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

78.1 mg of m-chloroperbenzoic acid was added to chloroform (10 mL)solution of 111.2 mg of the compound obtained in the above 1, andstirred at room temperature for 15 minutes. The reaction liquid waswashed with aqueous saturated sodium hydrogencarbonate solution, anddried with anhydrous sodium sulfate. The solvent was evaporated awayunder reduced pressure to obtain crude2-benzyl-6-(methylsulfinyl)-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneas a white solid.

30 mg of 4-[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)]aniline and0.05 mL of N,N-diisopropylethylamine were added to toluene (5 mL)solution of the above compound, and stirred at 120° C. for 15 hours. Thesolvent was evaporated away under reduced pressure, water was added tothe residue, extracted with ethyl acetate and dried with anhydroussodium sulfate. The solvent was evaporated away under reduced pressure,and the residue was separated and purified through basic silica gelcolumn chromatography (ethyl acetate) to obtain 22.6 mg of the entitledcompound as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 8.58 (1H, m), 7.81 (1H, t,J=3.8 Hz), 7.68 (1H, d, J=3.8 Hz), 7.43 (1H, bs), 6.92-7.40 (8H, m),5.37 (2H, s), 2.92-2.99 (4H, bs), 2.57-2.77 (4H, bs), 2.42 (3H, s), 2.29(3H, s).

ESI-MS Found: m/z [M+H]+ 507.

EXAMPLE 136 Production of2-(2-chlorophenyl)-1-[6-(1-hydroxycyclobutyl)pyridin-2-yl]-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of 1-[6-(tributylstannyl)pyridin-2-yl]cyclobutanol

Tetrahydrofuran (10 mL) solution of 293.1 mg of1-(6-bromo-2-pyridinyl)cyclobutanol obtained in Example 69-1 was cooledto −78° C. in an acetone/dry ice bath in a nitrogen atmosphere, and 1.8mL of 1.58 M n-butyllithium/hexane solution was gradually added thereto,and stirred for 30 minutes. Subsequently, tetrahydrofuran (2.0 mL)solution of 0.36 mL of tri-n-butyltin chloride was added thereto at −78°C., and the reaction solution was stirred for 30 minutes. This wasprocessed with aqueous saturated ammonium chloride solution, extractedwith ethyl acetate, and the organic layer was washed with saturatedsaline water, and purified through silica gel column chromatography(hexane/ethyl acetate) to obtain 48.7 mg of the entitled compound as apale yellow oily substance.

ESI-MS Found: m/z [M+H]+ 439.

2) Production of2-(2-chlorophenyl)-1-[6-(1-hydroxycyclobutyl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

6.7 mg of the entitled compound was obtained as a pale yellow solid inthe same manner as in Example 135-2, for which, however, the compoundobtained in the above reaction was used in place of2-(tributylstannyl)pyridine used in Example 135-2.

ESI-MS Found: m/z [M+H]+ 440.

3) Production of2-(2-chlorophenyl)-1-[6-(1-hydroxycyclobutyl)pyridin-2-yl]-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

3.4 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 1-2 to 1-3, for which, however, the compoundobtained in the above was used in place of the starting compound used inExample 1-2, and 3-methyl-4-(4-methylpiperazin-1-yl)aniline was used inplace of 4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.92 (1H, s), 7.99 (1H, d, J=8.3 Hz), 7.83(1H, dd, J=7.8, 3.9 Hz), 7.62-7.45 (3H, m), 7.47-7.35 (2H, m), 7.34-7.20(3H, m), 7.06 (1H, d, J=8.8 Hz), 3.07-2.93 (4H, m), 2.80-2.55 (3H, m),2.43 (3H, s), 2.35 (3H, s), 2.33-2.08 (3H, m), 2.03-1.89 (1H, m),1.75-1.58 (1H, m), 1.33-1.19 (2H, m).

ESI-MS Found: m/z [M+H]+ 598.

EXAMPLE 137 Production of1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-2-isopropyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

35 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-2 to 53-3, for which, however,2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Production Example 3 was used in place of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 53-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.77 (1H, s), 7.88 (1H, dd, J=8.0, 7.6 Hz),7.67 (1H, d, J=7.6 Hz), 7.44 (2H, d, J=8.0 Hz), 7.35 (1H, d, J=8.0 Hz),6.92 (2H, d, J=8.0 Hz), 4.24 (1H, septet, J=6.8 Hz), 3.21 (4H, m), 2.61(4H, m), 2.38 (3H, s), 1.58 (6H, s), 1.48 (6H, s).

ESI-MS Found: m/z [M+H]+ 503.

EXAMPLE 138 Production of1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-2-isopropyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

55 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-2 to 53-3, for which, however,2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Production Example 3 was used in place of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 53-2, 2-(6-bromopyridin-2-yl)-2-methylpropan-1-olobtained in Example 103-1 was used in place of2-(6-bromo-2-pyridinyl)-2-propanol used in Example 53-2, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.79 (1H, s), 7.82 (1H, dd, J=8.0, 8.0 Hz),7.56 (1H), 7.37-7.32 (2H), 7.30-7.24 (1H), 7.01 (1H, d, J=8.8 Hz), 3.81(1H, d, J=7.2 Hz), 2.94 (4H, m), 2.62 (4H, m), 2.39 (3H, s), 2.30 (3H,s), 1.52 (6H, d, J=7.2 Hz), 1.39 (6H, s).

ESI-MS Found: m/z [M+H]+ 531.

EXAMPLE 139 Production of1-[6-(2-hydroxy-1,1-dimethylethyl)pyridin-2-yl]-2-isopropyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

43 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-2 to 53-3, for which, however,2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Production Example 3 was used in place of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 53-2, and 2-(6-bromopyridin-2-yl)-2-methylpropan-1-olobtained in Example 103-1 was used in place of2-(6-bromo-2-pyridinyl)-2-propanol used in Example 53-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.78 (1H, s), 7.83 (1H, dd, J=8.0, 8.0 Hz),7.58 (1H, d, J=2.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.25 (1H, d, J=8.0 Hz),6.91 (2H, J=8.8 Hz), 4.12 (1H, septet, J=6.8 Hz), 3.82 (2H, s), 3.20(4H, m), 2.61 (4H, m), 2.37 (3H, s), 1.52 (6H, d, J=6.8 Hz), 1.39 (6H,s).

ESI-MS Found: m/z [M+H]+ 517.

EXAMPLE 140 Production of2-isopropyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

14.5 mg of the entitled compound was obtained as a yellow solid in thesame manner as in Example 53-2 to 53-3, for which, however,2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneobtained in Production Example 3 was used in place of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 53-2, 2-bromopyridin was used in place of2-(6-bromo-2-pyridinyl)-2-propanol used in Example 53-2, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 53-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.78 (1H, s), 8.57 (1H, d, J=4.9 Hz), 7.88(1H, td, J=7.8, 1.8 Hz), 7.73 (1H, d, J=8.3 Hz), 7.59-7.20 (2H, m), 7.00(1H, d, J=8.8 Hz), 4.33-4.26 (1H, m), 2.95 (4H, t, J=4.6 Hz), 2.82-2.49(4H, m), 2.40 (3H, s), 2.30 (3H, s), 1.44 (6H, d, J=6.8 Hz).

ESI-MS Found: m/z [M+H]+ 459.

EXAMPLE 141 Production of3-chloro-2-(1-(6-chloropyridin-2-yl)-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)benzonitrile 1)Production of acetone(6-chloropyridin-2-yl)hydrazone

Acetone was added to 2-chloro-6-hydrazone and concentrated under reducedpressure to obtain 3.10 g of the entitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 7.67 (1H, brs), 7.49 (1H, t, J=7.8 Hz), 7.10(1H, d, J=8.2 Hz), 6.72 (1H, d, J=7.4 Hz), 2.05 (3H, s), 1.88 (3H, s).

ESI-MS Found: m/z [M+H]+ 184, 186.

2) Production ofacetone(6-chloropyridin-2-yl)[5-iodo-2-(methylthio)pyrimidin-4-yl]hydrazone

With cooling with ice, 48 mg of sodium hydride (55% to 72%) was added toN,N-dimethylformamide (5.0 mL) solution of 367 mg of the above compoundand 287 mg of 4-chloro-5-iodo-2-(methylthio)pyrimidine. After stirredfor 3 hours, water was added to the reaction liquid, and extracted withethyl acetate. This was washed with water and saturated saline water,dried with anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified through silica gel columnchromatography (hexane/ethyl acetate=9/1 to 4/1) to obtain 128 mg of theentitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.67 (1H, s), 7.62 (1H, t, J=8.0 Hz), 7.02(1H, d, J=7.8 Hz), 6.92 (1H, d, J=8.0 Hz), 2.40 (3H, s), 2.22 (3H, s),1.72 (3H, s).

ESI-MS Found: m/z [M+H]+ 434, 436.

3) Production of4-[1-(6-chloropyridin-2-yl)hydrazino]-5-iodo-2-(methylthio)pyrimidine

One mL of 2 N hydrochloric acid was added to methanol (2 mL) solution of200 mg of the above compound, and stirred overnight. 2 mL of 2 Nhydrochloric acid was further added thereto, and stirred for 4 days.Then, aqueous sodium carbonate solution was added to the reactionliquid, and extracted with ethyl acetate. This was washed with saturatedsaline water, dried with anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was purified through silica gelcolumn chromatography (hexane/ethyl acetate=6/1 to 5/1) to obtain 129 mgof the entitled compound as a white solid.

ESI-MASS (m/e): 392, 394(M+H).

4) Production of methyl2-(6-chloropyridin-2-yl)-2-[5-iodo-2-(methylthio)pyrimidin-4-yl]hydrazinecarboxylate

With cooling with ice, 0.1 mL of methyl chlorocarbonate was added to asolution of 129 mg of the above compound in 2.0 mL of chloroform and 1mL of pyridine, and stirred for 50 minutes. Water was added to thereaction liquid, and extracted with ethyl acetate. This was washed withaqueous 10% phosphoric acid solution, saturated sodiumhydrogencarbonate, and saturated saline water, dried with anhydrousmagnesium sulfate, and concentrated under reduced pressure. 147 mg ofthe entitled compound was thus obtained as a white solid.

5) Production of methyl1-(2-chloro-6-cyanophenyl)-2-(6-chloropyridin-2-yl)-2-[5-iodo-2-(methylthio)pyrimidin-4-yl]hydrazinecarboxylate

N-methylpyrrolidone (2.5 mL) solution of 147 mg of the above compound,90 mg of potassium carbonate and 67 mg of 3-chloro-2-fluorobenzonitrilewas stirred at 90° C. for 3 hours. Water was added to the reactionliquid, and extracted with ethyl acetate. This was washed with water andsaturated saline water, dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified throughsilica gel column chromatography (hexane/ethyl acetate=80/20) to obtain62.1 mg of the entitled compound as a white amorphous substance.

ESI-MS Found: m/z [M+H]+ 587, 589.

6) Production of3-chloro-2-[1-(6-chloropyridin-2-yl)-6-(methylthio)-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl]benzonitrile

With cooling with ice, 0.1 mL of 2.0 M isopropylmagnesiumchloride/tetrahydrofuran solution was added to tetrahydrofuran (3.0 mL)solution of 62 mg of the above compound, and stirred for 15 minutes.Water was added to the reaction liquid, and 20, extracted with ethylacetate. This was washed with saturated saline water, dried withanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue was purified through basic silica gel column chromatography(hexane/chloroform=90/10 to 2/1), and crystallized from diethyl ether toobtain 8.5 mg of the entitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 9.04 (1H, s), 8.19 (1H, d, J=8.2 Hz), 7.77(1H, t, J=8.0 Hz), 7.74 (1H, dd, J=7.8, 1.4 Hz), 7.48 (1H, d, J=8.0 Hz),7.10 (1H, d, J=7.8 Hz), 2.68 (3H, s).

ESI-MS Found: m/z [M+H]+ 429, 431.

7) Production of3-chloro-2-(1-(6-chloropyridin-2-yl)-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)benzonitrile

3 mL of toluene and 8.5 mg of m-chloroperbenzoic acid (>65%) were addedto 8.5 mg of the compound obtained in the above, and stirred for 40minutes. 0.05 mL of N,N-diisopropylethylamine and 5 mg of3-methyl-4-(4-methylpiperazin-1-yl)aniline were added to the reactionliquid, and stirred overnight. Aqueous saturated sodiumhydrogencarbonate solution was added to the reaction liquid, andextracted with ethyl acetate. This was dried with anhydrous magnesiumsulfate, the solvent was evaporated away under reduced pressure, and theresidue was purified through basic silica gel column chromatography(hexane/ethyl acetate=2/1 to 0/100) to obtain 7.06 mg of the entitledcompound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.93 (1H, s), 8.17 (1H, d, J=6.2 Hz),7.73-7.63 (4H, m), 7.50 (1H, brs), 7.44 (1H, dd, J=8.2, 7.8 Hz), 7.34(1H, d, J=6.0 Hz), 7.08-7.04 (2H, m), 2.97 (4H, t, J=4.6 Hz), 2.62 (4H,brs), 2.39 (3H, s), 2.34 (3H, s).

ESI-MS Found: m/z [M+H]+ 586, 588.

EXAMPLE 142 Production of3-chloro-2-(1-methyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)benzonitrile 1)Production of 5-iodo-4-(1-methylhydrazino)-2-(methylthio)pyrimidine

603 mg of potassium carbonate was added to ethanol (15 mL) solution of1.25 g of 4-chloro-5-iodo-2-(methylthio)pyrimidine, and with coolingwith ice, 0.28 mL of methylhydrazine was dropwise added thereto. Thiswas stirred overnight at room temperature, then water was added thereto,and the precipitated crystal was taken out through filtration and driedto obtain 851 mg of the entitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.43 (1H, s), 4.16 (2H, brs), 3.37 (3H, s),2.49 (3H, s).

ESI-MS Found: m/z [M+H]+ 297.

2) Production of methyl2-[5-iodo-2-(methylthio)pyrimidin-4-yl]-2-methylhydrazinecarboxylate

0.05 mL of methyl chlorocarbonate was added to pyridine (2 mL) solutionof 160 mg of the above compound, stirred overnight, and then 0.08 mL ofmethyl chlorocarbonate was further added thereto. The reaction liquidwas concentrated under reduced pressure, water was added thereto, andextracted with ethyl acetate. This was washed with saturated salinewater, dried with anhydrous magnesium sulfate, and concentrated underreduced pressure to obtain 132 mg of the entitled compound as a whitesolid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.47 (1H, s), 6.95 (1H, brs), 3.78 (3H, s),3.37 (3H, s), 2.50 (3H, s).

ESI-MS Found: m/z [M+H]+ 355.

3) Production of methyl1-(2-chloro-6-cyanophenyl)-2-[5-iodo-2-(methylthio)pyrimidin-4-yl]-2-methylhydrazinecarboxylate

N-methylpyrrolidone (1 mL) solution of 36 mg of the above compound, 26mg of potassium carbonate and 20 mg of 3-chloro-2-fluorobenzonitrile wasstirred overnight at 90° C. Water was added to the reaction liquid, andextracted with ethyl acetate. This was washed with water and saturatedsaline water, dried with anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was purified through silica gelcolumn chromatography (hexane/ethyl acetate=10/1 to 6/1) to obtain 32 mgof the entitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.57 (1H, s), 7.70 (1H, dd, J=8.2, 1.4 Hz),7.65 (1H, dd, J=7.8, 1.4 Hz); 7.37 (1H, dd, J=8.2, 7.8 Hz), 3.89 (3H,s), 3.61 (3H, s), 2.47 (3H, s).

ESI-MS Found: m/z [M+H]+ 490, 492.

4) Production of3-chloro-2-[1-methyl-6-(methylthio)-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl]benzonitrile

With cooling with ice, 0.1 mL of 2.0 M isopropylmagnesiumchloride/tetrahydrofuran solution was added to tetrahydrofuran (2.0 mL)solution of 56 mg of the above compound, and stirred for 1 hour. Waterwas added to the reaction liquid, and extracted with methyl acetate.This was washed with saturated saline water, dried with anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residuewas purified through silica gel column chromatography (hexane/ethylacetate=6/1 to 2/1) to obtain 12.2 mg of the entitled compound as awhite solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.92 (1H, s), 7.84 (1H, dd, J=8.2, 1.4 Hz),7.79 (1H, dd, J=7.8, 1.4 Hz), 7.62 (1H, dd, J=8.2, 7.8 Hz), 3.39 (3H,s), 2.64 (3H, s).

ESI-MS Found: m/z [M+H]+ 332, 334.

5) Production of3-chloro-2-(1-methyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)benzonitrile

11.1 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 141-7, for which, however, 12.2 mg of thecompound obtained in the above was used in place of3-chloro-2-(1-(6-chloropyridin-2-yl)-6-(methylthio)-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)benzonitrileused in Example 141-7.

¹H-NMR (400 MHz, CDCl₃) δ: 8.84 (1H, s), 7.80 (1H, d, J=8.2 Hz), 7.77(1H, dd, J=7.8, 1.4 Hz), 7.58 (1H, dd, J=8.2, 7.8 Hz), 7.55 (1H, brs),7.45 (1H, brs), 7.37 (1H, d, J=2.5 Hz), 7.07 (1H, d, J=8.8 Hz), 3.32(3H, s), 2.96 (4H, t, J=4.7 Hz), 2.61 (4H, brs), 2.38 (3H, s), 2.33 (3H,s).

ESI-MS Found: m/z [M+H]+ 489, 491.

EXAMPLE 143 Production of2-(1-methyl-6-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)benzonitrile 1)Production of2-{2-[5-iodo-2-(methylthio)pyrimidin-4-yl]-2-methylhydrazino}benzonitrile

N-methylpyrrolidone (5 mL) solution of 443 mg of the compound obtainedin Example 142-2, 519 mg of potassium carbonate and 0.679 mL of2-fluorobenzonitrile was stirred overnight at 90° C. Water was added tothe reaction liquid, and extracted with ethyl acetate. This was washedwith water and saturated saline water, dried with anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue waspurified through silica gel column chromatography (hexane/ethylacetate=19/1 to 2/1) to obtain 125 mg of the entitled compound as awhite solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.50 (1H, s), 7.53 (1H, d, J=7.8 Hz), 7.48(1H, dd, J=8.0, 7.8 Hz), 6.94 (1H, dd, J=7.8, 7.4 Hz), 6.81 (1H, d,J=8.6 Hz), 6.65 (1H, brs), 3.41 (3H, s), 2.53 (3H, s).

ESI-MS Found: m/z [M+H]+ 397.

2) Production of2-[1-methyl-6-(methylthio)-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl]benzonitrile

Dioxane (5 mL) solution of 125 mg of the compound obtained in the abovereaction, 25 mg ofdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethaneadduct and 50 mg of sodium hydrogencarbonate was stirred in a carbonmonoxide atmosphere under a pressure of 4 atmospheres at 90° C. for 6hours. The reaction liquid was filtered, the filtrate was concentratedand purified through silica gel column chromatography (hexane/ethylacetate=4/1 to 1/1) to obtain 22.7 mg of the entitled compound as awhite solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.92 (1H, s), 7.86 (1H, dd, J=7.8, 1.0 Hz),7.76 (1H, td, J=8.0, 1.5 Hz), 7.54 (1H, td, J=7.8, 1.0 Hz), 7.44 (1H,dd, J=8.0, 0.7 Hz), 3.40 (3H, t, J=13.7 Hz), 2.65 (3H, t, J=13.7 Hz).

ESI-MS Found: m/z [M+H]+ 298.

3) Production of2-(1-methyl-6-([3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino)-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)benzonitrile

12.1 mg of the entitled compound was obtained as a white solid in thesame manner as in Example 141-7, for which, however, 16 mg of thecompound obtained in the above reaction was used in place of3-chloro-2-(1-(6-chloropyridin-2-yl)-6-(methylthio)-3-oxo-1,3-dihydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)benzonitrileused in Example 141-7.

¹H-NMR (400 MHz, CDCl₃) δ: 8.82 (1H, s), 7.83 (1H, dd, J=7.6, 1.2 Hz),7.72 (1H, td, J=7.8, 1.5 Hz), 7.56-7.37 (4H, m), 7.07 (1H, d, J=8.3 Hz),3.34 (3H, s), 2.96 (4H, t, J=4.6 Hz), 2.61 (4H, brs), 2.38 (3H, s), 2.34(3H, s).

ESI-MS Found: m/z [M+H]+ 455.

EXAMPLE 144 Production of6-(2-chlorophenyl)-2-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one 1)Production of ethyl4-(chloromethyl)-2-(methylthio)pyrimidine-5-carboxylate

60 mL of ethyl triethylorthoformate and 70 mL of acetic anhydride wereadded to 30.4 g of ethyl 4-chloro-3-oxobutanoate, and the resultingreaction solution was stirred under heat at 110° C. for 3 hours. Thesolvent was evaporated away under reduced pressure, 100 mL of n-hexanewas added to the residue, and the formed, pale yellow needle-likecrystal was taken out through filtration and dried to obtain 19.5 g ofcrude ethyl 4-chloro-2-(ethoxymethylene)-2-oxobutanoate.

A solution of 1.81 g of sodium hydroxide in 20 mL of water was added totetrahydrofuran (100 mL) suspension of 6.31 g of methylimidothiocarbamate 0.5-sulfate, and stirred at room temperature for 10minutes. Tetrahydrofuran (100 mL) solution of 10.0 g of the crudeproduct obtained in the above was added to the resulting solution, andstirred at room temperature for 10 minutes. The reaction solution waspartitioned between ethyl acetate and water, the organic layer waswashed with saturated saline water, dried with magnesium sulfate, andthe solvent was evaporated away under reduced pressure. The residue waspurified through silica gel column chromatography (hexane/ethyl acetate)to obtain 7.60 g of the entitled compound as a yellow amorphoussubstance.

¹H-NMR (400 MHz, CDCl₃) δ: 9.04 (1H, s), 4.97 (1H, s), 4.44 (2H, q,J=7.0 Hz), 2.63 (3H, s), 1.42 (3H, t, J=7.0 Hz).

ESI-MS Found: m/z [M+H]+ 389.

2) Production of ethyl4-{[(2-chlorophenyl)amino]methyl}-2-(methylthio)pyrimidine-5-carboxylate

0.15 mL of 2,6-lutidine and 0.13 mL of 2-chloroaniline were added to 3.0mL of an ethanol solution of 205 mg of the compound obtained in theabove, and heated under reflux for 18 hours. The reaction solution wascooled to room temperature, and the resulting colorless solid was takenout through filtration and washed with ethanol to obtain 169 mg of theentitled compound.

¹H-NMR (400 MHz, CDCl₃) δ: 9.02 (1H, s), 7.28 (1H, dd, J=7.8, 1.5 Hz),7.17 (1H, ddd, J=7.8, 7.3, 1.4 Hz), 6.79 (1H, dd, J=6.8, 1.4 Hz), 6.66(1H, ddd, J=7.3, 6.8, 1.4 Hz), 4.84 (2H, s), 4.43 (2H, q, J=7.0 Hz),2.66 (3H, s), 1.44 (3H, t, J=7.0 Hz).

ESI-MS Found: m/z [M+H]+ 338.

3) Production of6-(2-chlorophenyl)-2-(methylthio)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one

3 mL of aqueous 2 N sodium hydroxide solution was added to methanol (3mL) solution of 741 mg of the compound obtained in the above reaction,and stirred at room temperature for 18 hours. This was made acidic with2 N hydrochloric acid added thereto, extracted with chloroform, then theorganic layer was washed with saturated saline water and dried withmagnesium sulfate, and the solvent was evaporated away under reducedpressure to obtain 684 mg of crude4-{[(2-chlorophenyl)amino]methyl}-2-(methylthio)pyrimidine-5-carboxylicacid.

The crude product was dissolved in 3.0 mL of N,N-dimethylformamide, and86 mg of 1-hydroxybenzotriazole and 108 mg of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were addedthereto and stirred at room temperature for 3 hours. Ethyl acetate andwater were added to the reaction solution for partition, the organiclayer was washed with water and then with saturated saline water, anddried with magnesium sulfate. The solvent was evaporated away underreduced pressure, and the residue was purified through silica gel columnchromatography (hexane/ethyl acetate) to obtain 42.0 mg of the entitledcompound as a colorless amorphous substance.

¹H-NMR (400 MHz, CDCl₃) δ: 9.00 (1H, s), 7.56-7.44 (1H, m), 7.42-7.31(3H, m), 4.80 (2H, s), 2.66 (3H, s).

ESI-MS Found: m/z [M+H]+ 292.

4) Production of6-(2-chlorophenyl)-2-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one

19.2 mg of the entitled compound was obtained as a pale yellow solid inthe same manner as in Example 1-2 to 1-3, for which, however, thecompound obtained in the above reaction was used in place of thestarting compound in Example 1-2, and3-methyl-4-(4-methylpiperazin-1-yl)aniline was used in place of4-(4-methylpiperazin-1-yl)aniline used in Example 1-3.

¹H-NMR (400 MHz, CDCl₃) δ: 8.87 (1H, s), 7.55-7.34 (7H, m), 7.06 (1H, d,J=8.4 Hz), 4.71 (2H, s), 2.96-2.93 (4H, m), 2.60-2.47 (4H, m), 2.37 (3H,s), 2.33 (3H, s).

ESI-MS Found: m/z [M+H]+ 429.

EXAMPLE 145 Production of6-benzyl-2-{[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one

4.0 mg of the entitled compound was obtained as a pale yellow solid inthe same manner as in Example 144-2 to 144-4, for which, however,benzylamine was used in place of 2-chloroaniline used in Example 144-2.

¹H-NMR (400 MHz, CDCl₃) δ: 8.79 (1H, s), 7.43-7.29 (8H, m), 7.03 (1H, d,J=8.4 Hz), 4.75 (2H, s), 4.17 (2H, s), 2.98-2.92 (4H, m), 2.75-2.57 (4H,m), 2.38 (3H, s), 2.30 (3H, s).

ESI-MS Found: m/z [M+H]+ 449.

EXAMPLE 146 Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[4,3-c]pyridin-2-one 1)Production of ethyl4-[2-allyl-2-(tert-butoxycarbonyl)hydrazino]-6-chloronicotinate

7.0 mL of N,N-diisopropylethylamine was added to tetrahydrofuran (70 mL)solution of 4.40 g of ethyl 4,6-dichloronicotinate and 3.44 g oftert-butyl 1-allylhydrazinecarboxylate obtained in Production Example1-1, and stirred overnight at 70° C. 30 mL of toluene was added to thereaction liquid, and tetrahydrofuran was evaporated away. This wasstirred at 120° C. for 6 hours, and then heated overnight under reflux.The reaction liquid was restored to room temperature, water was addedthereto, and extracted with ethyl acetate. This was washed withsaturated saline water, dried with anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was purified throughsilica gel column chromatography (hexane/ethyl acetate=16/1 to 12/1) toobtain 1.29 g of the entitled compound as a colorless oily substance.

¹H-NMR (400 MHz, CDCl₃) δ: 9.47 (1H, s), 8.74 (1H, s), 6.75 (1H, s),5.93-5.78 (1H, m), 5.28-5.15 (2H, m), 4.37 (2H, q, J=7.2 Hz), 4.00 (2H,d, J=5.9 Hz), 1.43 (9H, s), 1.40 (3H, t, J=7.3 Hz).

ESI-MS Found: m/z [M+H]+ 356, 358.

2) Production of2-allyl-6-chloro-1,2-dihydro-3H-pyrazolo[4,3-c]pyrimidin-3-one

739 mg of the entitled compound was obtained as a white solid in thesame manner as in Production Example 1-2, for which, however, 1.29 g ofthe compound obtained in the above reaction was used in place oftert-butyl 1-allylhydrazinecarboxylate used in Production Example 1-2.

¹H-NMR (400 MHz, CDCl₃) δ: 9.20 (1H, s), 7.30 (1H, s), 5.97 (1H, ddt,J=17.1, 10.2, 6.3 Hz), 5.33 (1H, dd, J=10.2, 1.0 Hz), 531 (1H, dd,J=17.1, 1.0 Hz), 4.76 (2H, d, J=6.3 Hz).

ESI-MS Found: m/z [M+H]+ 210, 212.

3) Production of2-allyl-6-chloro-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyridin-3-one

47 mg of the entitled compound was obtained in the same manner as inExample 29-1, for which, however, the compound obtained in the abovereaction was used in place of 2-iodopyridine used in Example 29-1.

¹H-NMR (400 MHz, CDCl₃) δ: 8.91 (1H, d, J=1.0 Hz), 7.93 (1H, t, J=7.8Hz), 7.54-7.52 (2H, m), 7.12 (1H, dd, J=7.8, 1.0 Hz), 5.72 (1H, ddt,J=17.1, 10.2, 6.2 Hz), 5.11 (1H, dd, J=10.2, 1.5 Hz), 4.98 (1H, dd,J=17.1, 1.0 Hz), 4.60 (2H, dt, J=6.2, 1.3 Hz), 3.69 (1H, s), 1.65 (6H,s).

ESI-MS Found: m/z [M+H]+ 345, 347.

4) Production of2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[4,3-c]pyridin-2-one

0.07 mL of diisopropylethylamine was added to toluene (5.0 mL) solutionof 46 mg of the compound obtained in the above reaction and 51 mg of4-(4-methylpiperazin-1-yl)aniline, and stirred at 200° C. for 3 days ina pressure reactor tube. The reaction liquid was restored to roomtemperature, concentrated, and the residue was purified through basicsilica gel chromatography (hexane/ethyl acetate=1/1 to ethyl acetate toethyl acetate/ethanol=49/1) and through silica gel chromatography(chloroform/methanol=29/1) to obtain 6.2 mg of the entitled compound asa yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.70 (1H, s), 7.78 (1H, t, J=7.8 Hz), 7.30(1H, d, J=7.3 Hz), 7.17 (2H, d, J=8.8 Hz), 6.96-6.86 (5H, m), 5.73 (1H,ddt, J=17.1, 10.2, 6.3 Hz), 5.09 (1H, d, J=10.2 Hz), 5.02 (1H, dd,J=17.1, 1.0 Hz), 4.43 (2H, d, J=6.3 Hz), 3.25 (4H, t, J=4.9 Hz), 2.66(4H, t, J=4.9 Hz), 2.41 (3H, s), 1.44 (6H, s).

ESI-MS Found: m/z [M+H]+ 500.

EXAMPLE 147 Production of1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-2-isopropyl-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

In the same manner as in Example 29-1 to 29-2, but using2-isopropyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onesynthesized in Production Example 3 in place of2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-oneused in Example 29-1, using 2-(6-bromo-2-pyridinyl)-2-propanolsynthesized in Example 53-1 in place of 2-iodopyridine and using4-(1-methylpiperazin-4-yl)aniline in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2,39.9 mg of the entitled compound was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.80 (1H, s), 7.88 (1H, t, J=7.8 Hz), 7.69(1H, d, J=7.8 Hz), 7.50 (3H, d, J=8.3 Hz), 7.38 (1H, d, J=7.8 Hz), 7.20(2H, d, J=8.3 Hz), 4.26 (1H, t, J=6.8 Hz), 4.18 (1H, s), 2.98 (2H, d,J=11.7 Hz), 2.52-2.43 (1H, m), 2.33 (3H, s), 2.09-2.02 (2H, m),1.86-1.77 (4H, m), 1.58 (6H, s), 1.48 (6H, d, J=6.8 Hz).

ESI-MS Found: m/z [M+H] 502.

EXAMPLE 148 Production of2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one 1)Production of2-allyl-1-(6-bromopyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

In the same manner as in Example 29-1, but using 2,6-dibromopyridin inplace of 2-iodopyridin used in Example 29-1, 2.94 g of the entitledcompound was obtained as a white solid.

¹H-NMR (400 MHz, CDCl₃)

δ: 8.94 (1H, s), 7.95 (1H, d, J=7.8 Hz), 7.73 (1H, t, J=8.0 Hz), 7.43(1H, d, J=7.8 Hz), 5.69 (1H, ddt, J=17.1, 10.2, 6.3 Hz), 5.06 (1H, dd,J=10.2, 1.2 Hz), 5.00 (1H, d, J=17.1 Hz), 4.88 (2H, d, J=6.3 Hz), 2.60(3H, s).

2) Production of2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

1-methylimidazolidin-2-one (96 mg), copper iodide (76 mg), potassiumcarbonate (110 mg) and N,N′-dimethylethane-1,2-diamine (85 μL) wereadded to a dioxane solution (5 mL) of2-allyl-1-(6-bromopyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one(150 mg), and stirred overnight in a sealed tube under heat at 100° C.

The reaction liquid was cooled, aqueous ammonia solution was added toit, and extracted three times with chloroform. The organic layer waswashed with saturated saline water, dried with anhydrous magnesiumsulfate, filtered, and the solvent was evaporated away. The obtainedcrude product was purified through silica gel column chromatography toobtain 136.4 mg of the entitled compound as a white solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.92 (1H, s), 8.26 (1H, d, J=8.4 Hz), 7.81(1H, dd, J=8.4, 7.6 Hz), 7.41 (1H, d, J=7.6 Hz), 5.66 (1H, ddd, J=16.8,10.0, 6.4 Hz), 5.06 (1H, d, J=10.0 Hz), 4.95 (1H, d, J=16.8 Hz), 4.80(2H, d, J=6.4 Hz), 4.01 (2H, t, J=8.0 Hz), 3.51 (1H, t, J=8.0 Hz), 2.94(3H, s), 2.57 (3H, s).

ESI-MS Found: m/z [M+H] 398.

3) Production of2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one

In the same manner as in Example 29-2, but using4-(4-methylpiperazin-1-yl)aniline in place of[5-amino-2-(4-methylpiperazin-1-yl)phenyl]methanol used in Example 29-2and using2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-onein place of2-allyl-6-(methylthio)-1-pyridin-2-yl-3H-pyrazolo[3,4-d]pyrimidin-3-one,115.6 mg of the entitled compound was obtained as a yellow solid.

¹H-NMR (400 MHz, CDCl₃) δ: 8.81 (1H, s), 8.22 (1H, d, J=8.4 Hz), 7.78(1H, dd, J=8.4, 8.0 Hz), 7.46 (2H, d, J=8.0 Hz), 7.40 (1H, d, J=8.0 Hz),6.90 (2H, d, J=8.0 Hz), 5.68 (1H, ddd, J=16.8, 10.4, 6.0 Hz), 5.04 (1H,d, J=10.4 Hz), 4.95 (1H, d, J=16.8 Hz), 4.74 (2H, d, J=6.0 Hz), 4.02(2H, t, J=8.4 Hz), 3.49 (2H, t, J=8.4 Hz), 3.02 (4H, m), 2.94 (3H, S),2.60 (4H, m), 2.37 (3H, s).

ESI-MS Found: m/z [M+H] 541.

Similarly to the above-mentioned Examples and suitably usingcorresponding starting compounds, Compounds Nos. 1a to 189a shown in thefollowing Tables were obtained.

Compound No Structure 1a

2a

3a

4a

5a

6a

7a

8a

9a

10a

11a

12a

13a

14a

15a

16a

17a

18a

19a

20a

21a

22a

23a

24a

25a

26a

27a

28a

29a

30a

31a

32a

33a

34a

35a

36a

37a

38a

39a

40a

41a

42a

43a

44a

45a

46a

47a

48a

49a

50a

51a

52a

53a

54a

55a

56a

57a

58a

59a

60a

61a

62a

63a

64a

65a

66a

67a

68a

69a

70a

71a

72a

73a

74a

75a

76a

77a

78a

79a

80a

81a

82a

83a

84a

85a

86a

87a

88a

89a

90a

91a

92a

93a

94a

95a

96a

97a

98a

99a

100a

101a

102a

103a

104a

105a

106a

107a

108a

109a

110a

111a

112a

113a

114a

115a

116a

117a

118a

119a

120a

121a

122a

123a

124a

125a

126a

127a

128a

129a

130a

131a

132a

133a

134a

135a

136a

137a

138a

139a

140a

141a

142a

143a

144a

145a

146a

147a

148a

149a

150a

151a

152a

153a

154a

155a

156a

157a

158a

159a

160a

161a

162a

163a

164a

165a

166a

167a

168a

169a

170a

171a

172a

173a

174a

175a

176a

177a

178a

179a

180a

181a

182a

183a

184a

185a

186a

187a

188a

189a

The data of ¹H-NMR and MS spectrum on the above compounds are shown inthe below tables.

Compound ESI-MS No ¹H NMR (400 MHz) (M + H)+  1a (CDCl3) δ: 8.80 (1H,s), 7.45 (1H, bs), 7.42 (1H, t, J = 8.3 Hz), 474 7.30 (1H, d, J = 8.3Hz), 7.02 (1H, d, J = 8.3 Hz), 6.99 (1H, s), 6.95 (1H, d, J = 8.3 Hz),6.91 (1H, d, J = 8.3 Hz), 3.89 (2H, q, J = 6.9 Hz), 3.84 (3H, s),3.89-3.96 (4H, m), 2.54-2.72 (4H, m), 2.39 (3H, s), 2.28 (3H, s), 1.08(3H, t, J = 6.9 Hz).  2a (CDCl3) δ: 8.80 (1H, s), 7.59 (1H, bs), 7.37(1H, d, J = 9.3 Hz), 474 7.21-7.38 (1H, m), 7.04 (2H, d, J = 9.3 Hz),6.97 (1H, d, J = 8.8 Hz), 3.88 (3H, s), 3.83 (2H, q, J = 6.8 Hz),3.88-3.99 (4H, m), 3.52-3.77 (4H, m), 2.40 (3H, s), 2.27 (3H, s), 1.09(3H, t, J = 6.8 Hz).  3a (CD3OD) δ: 8.79 (1H, s), 7.65 (1H, d, J = 7.4Hz), 7.59-7.56 (2H, 444 m), 7.47-7.43 (2H, m), 7.41-7.33 (2H, m), 7.12(1H, d, J = 8.8 Hz), 3.62-3.55 (2H, m), 3.39-3.24 (7H, m), 3.11-3.01(2H, m), 2.98 (3H, s), 2.36 (3H, s), 2.26 (3H, s).  4a (CD3OD) δ: 8.78(1H, s), 7.69-7.63 (1H, m), 7.63-7.49 (3H, 448 m), 7.41-7.36 (2H, m),7.12 (1H, d, J = 8.6 Hz), 3.62-3.56 (2H, m), 3.38-3.24 (7H, m),3.10-3.02 (2H, m), 2.99 (3H, s), 2.36 (3H, s).  5a (CD3OD) δ: 8.74 (1H,s), 7.62-7.55 (1H, m), 7.53-7.48 (1H, 460 m), 7.15 (1H, d, J = 8.6 Hz),7.04 (1H, d, J = 8.6 Hz), 6.85-6.80 (1H, m), 6.78-6.71 (1H, m), 3.24(3H, s), 2.95-2.89 (4H, m), 2.68-2.56 (4H, m), 2.35 (3H, s), 2.30 (3H,s), 2.11 (3H, s).  6a (CDCl3) δ: 8.79 (1H, s), 7.24-7.57 (6H, m), 6.99(1H, d, J = 8.6 Hz), 469 3.89 (2H, t, J = 7.8 Hz), 2.94 (4H, t, J = 3.0Hz), 2.55-2.70 (4H, m), 2.39 (3H, s), 2.30 (3H, s), 1.09 (3H, t, J = 7.8Hz).  7a (CDCl3) δ: 8.81 (1H, s), 7.89 (1H, s), 7.61-7.71 (3H, m), 4507.22-7.27 (2H, m), 7.07 (1H, d, J = 8.9 Hz), 3.86 (2H, t, J = 7.4 Hz),2.93-2.99 (4H, m), 2.56-2.68 (4H, m), 2.38 (3H, s), 2.32 (3H, s), 1.07(3H, t, J = 7.4 Hz).  8a (DMSO-d6) δ: 8.78 (1H, s), 7.59-7.78 (1H, m),7.29-7.45 (5H, 458 m), 6.92 (1H, d, J = 8.3 Hz), 3.64-3.72 (2H, m), 2.77(4H, t, J = 3.1 Hz), 2.40-2.55 (4H, m), 2.37 (3H, s), 2.22 (3H, s), 2.18(3H, s), 0.95 (3H, t, J = 6.9 Hz).  9a (DMSO-d6) δ: 8.78 (1H, s),7.45-7.52 (2H, m), 7.12 (2H, s), 472 7.05 (1H, s), 6.92 (1H, d, J = 8.7Hz), 3.66-3.75 (2H, m), 2.77 (4H, bs), 2.39-2.50 (4h, m), 2.34 (6H, s),2.23 (3H, s), 2.17 (3H, s), 0.95 (3H, t, J = 7.4 Hz).  10a (DMSO-d6) δ:8.78 (1H, s), 7.59 (2H, d, J = 8.8 Hz), 7.45 (2H, d, 500 J = 8.8 Hz),7.21-7.32 (2H, m), 6.92 (1H, d, J = 8.7 Hz), 3.65-3.77 (2H, m),2.73-2.81 (4H, m), 2.38-2.55 (4H, m), 2.21 (3H, s), 2.17 (3H, s), 0.96(3H, t, J = 7.3 Hz).  11a (CDCl3) δ: 8.78 (1H, s), 7.31-7.55 (6H, m),6.97 (1H, d, J = 8.2 Hz), 474 4.79 (2H, s), 3.86 (2H, q, J = 7.2 Hz),2.87-2.94 (4H, m), 2.51-2.70 (4H, m), 2.36 (3H, s), 2.27 (3H, s), 1.07(3H, t, J = 7.2 Hz).  12a (CDCl3) δ: 8.80 (1H, s), 7.53 (2H, d, J = 8.0Hz), 7.48 (2H, d, J = 8.0 Hz), 474 6.97 (1H, d, J = 8.2 Hz), 4.78 (2H,s), 3.86 (2H, q, J = 7.2 Hz), 2.89-2.95 (4H, m), 2.56-2.71 (4H, m), 2.39(3H, s), 2.29 (3H, s), 1.07 (3H, t, J = 7.2 Hz).  13a (CDCl3) δ: 8.80(1H, s), 7.23-7.58 (7H, m), 6.98 (1H, d, J = 8.7 Hz), 444 3.88 (2H, q, J= 7.4 Hz), 2.90-2.98 (4H, m), 2.52-2.73 (4H, m), 2.40 (3H, s), 2.29 (3H,s), 1.08 (3H, t, J = 7.4 Hz).  14a (CDCl3) δ: 8.81 (1H, s), 7.20-7.58(5H, m), 6.99 (1H, d, J = 8.2 Hz), 462 5.66-5.78 (1H, m), 5.13 (1H, d, J= 9.3 Hz), 5.04 (1H, d, J = 17.0 Hz), 4.43 (2H, d, J = 7.6 Hz),2.89-2.96 (4H, m), 2.53-2.73 (4H, m), 2.38 (3H, s), 2.29 (3H, s).  15a(CDCl3) δ: 8.82 (1H, s), 8.13 (1H, s), 7.93 (1H, bs), 463 7.19-7.44 (3H,m), 5.67-5.77 (1H, m9, 5.15 (1H, d, J = 10.3 Hz), 5.06 (1H, d, J = 17.0Hz), 3.12-3.21 (4H, m), 2.58-2.69 (4H, m), 2.38 (3H, s), 2.27 (3H, s). 16a (DMSO-d6) δ: 8.79 (1H, s), 8.31 (1H, s), 7.28-7.80 (2H, m), 4647.28-7.38 (2H, m), 6.92 (1H, d, J = 8.7 Hz), 3.65-3.78 (2H, m),2.75-2.82 (4H, m), 2.38-2.53 (4H, m), 2.22 (3H, s), 2.19 (3H, s),1.39-1.49 (2H, m), 0.70 (3H, t, J = 7.3 Hz).  17a (CDCl3) δ: 8.88 (1H,s), 7.41-7.99 (9H, m), 7.07 (1H, d, J = 8.8 Hz), 480 3.25 (3H, s), 2.95(4H, m), 2.64 (4H, brs), 2.38 (3H, s), 2.34 (3H, s).  18a (CDCl3) δ:8.81 (1H, s), 7.21-7.57 (5H, m), 6.98 (1H, d, J = 8.3 Hz), 449 5.66-5.77(1H, m), 5.14 (1H, d, J = 9.3 Hz), 5.04 (1H, d, J = 17.1 Hz), 4.42 (2H,d, J = 5.9 Hz), 3.82-3.89 (4H, m), 2.86-2.93 (4H,), 2.31 (3H, s).  19a(CDCl3) δ: 8.84 (1H, s), 8.22 (1H, s), 7.62 (1H, bs), 471 7.22-7.46 (6H,m), 7.09 (1H, s), 6.84 (1H, d, J = 8.8 Hz), 5.68-5.78 (1H, m), 5.14 (1H,d, J = 10.3 Hz), 5.05 (1H, d, J = 17.1 Hz), 4.43 (2H, d < J = 5.9 Hz),2.54 (3H, s), 2.21 (3H, s).  20a (CDCl3) δ: 8.80 (1H, s), 7.30-8.45 (5H,m), 7.08 (1H, d, J = 8.0 Hz), 464 3.38 (3H, s), 2.96 (4H, m), 2.64 (4H,brs), 2.38 (3H, s), 2.34 (3H, s).  21a (CDCl3) δ: 8.82 (1H, s),7.18-7.66 (6H, m), 4.78 (2H, s), 492 3.74 (2H, d, J = 6.9 Hz), 3.02 (4H,s), 2.50-78 (4H, m), 2.39 (3H, s), 0.89-0.97 (1H, m), 0.38-0.44 (2H, m),0.17-0.21 (2H, m).  22a (CDCl3) δ: 9.82 (1H, bs), 8.84 (1H, s), 8.42(1H, bs), 7.77 (1H, bs), 491 7.64 (1H, bs), 7.44 (1H, s), 7.21-7.26 (2H,m), 5.82 (1H, bs), 5.67-5.77 (1H, m), 5.14 (1H, d, J = 10.2 Hz), 5.04(1H, d, J = 17.1 Hz), 4.44 (2H, d, J = 5.9 Hz), 2.99-3.09 (4H, bs),2.51-2.79 (4H, bs), 2.40 (3H, s).  23a (CDCl3) δ: 8.83 (1H, s),7.21-7.78 (6H, m), 5.68-5.77 (1H, 535 m), 5.01-5.17 (2H, m), 5.43 (2H,d, J = 5.6 Hz), 3.88 (2H, t, J = 3.9 Hz), 3.67 (2H, t, J = 3.9 Hz),3.00-3.11 (4H, m), 2.55-2.83 (4H, m), 2.42 (3H, s).  24a (CDCl3) δ: 8.83(1H, s), 8.24 (1H, s), 7.10-7.93 (8H, m), 487 6.80 (1H, d, J = 8.8 Hz),5.65-5.78 (1H, m), 5.13 (1H, d, J = 10.2 Hz), 5.04 (1H, d, J = 17.0 Hz),4.72 (2H, s), 4.42 (2H, d, J = 5.8 Hz), 2.54 (3H, s).  25a (CDCl3) δ:8.74 (1H, s), 7.43-7.33 (2H, m), 7.29-7.25 (1H, 476 m), 7.21-7.15 (1H,m), 7.13-7.08 (1H, m), 6.53 (1H, d, J = 8.6 Hz), 5.73-5.62 (1H, m), 5.09(1H, d, J = 10.2 Hz), 5.03-4.97 (1H, m), 4.37 (2H, d, J = 4.7 Hz),3.36-3.24 (1H, m), 2.89-2.75 (2H, m), 2.31 (3H, s), 2.23-2.12 (2H, m),2.10-2.02 (5H, m), 1.60-1.45 (2H, m).  26a (CDCl3) δ: 8.82 (1H, s),7.21-7.69 (5H, m), 6.93 (1H, d, J = 7.8 Hz), 476 5.66-5.77 (1H, m), 5.13(1H, d, J = 10.0 Hz), 5.03 (1H, d, J = 16.9 Hz), 4.42 (2H, d, J = 6.1Hz), 3.60 (2H, s), 3.43 (2H, t, J = 6.2 Hz), 3.16 (2H, t, J = 6.2 Hz),3.04 (3H, s), 2.30 (3H, s).  27a (CDCl3) δ: 8.83 (1H, s), 7.03-7.78 (6H,m), 5.66-5.77 (1H, 492 m), 5.13 (1H, d, J = 10.1 Hz), 5.03 (1H, d, J =17.0 Hz), 4.74 (2H, s), 4.42 (2H, d, J = 5.9 Hz), 3.63 (2H, s),3.41-3.47 (2H, m), 3.20-3.26 (2H, m), 3.04 (3H, s).  28a (CDCl3) δ: 8.92(1H, s), 7.28-7.71 (6H, m), 4.88 (2H, s), 506 4.06 (2H, t, J = 7.3 Hz),3.11-3.13 (4H, m), 2.60-2.85 (4H, m), 2.49 (3H, s), 1.53 (2H, q, J = 7.3Hz), 1.60-1.70 (1H, m), 1.45-1.49 (2H, m), −0.5-−0.4 (2H, m).  29a(CDCl3) δ: 8.83 (1H, s), 7.50-7.70 (1H, m), 7.52 (1H, t, J = 8.4 Hz),491 7.44 (1H, t, J = 3.4 Hz), 7.29-7.38 (1H, m), 7.23 (1H, d, J = 4.5Hz), 7.18 (1H, d, J = 8.7 Hz), 4.76 (2H, s), 4.10 (2H, t, J = 6.6 Hz),3.00 (4H, t, J = 4.7 Hz), 2.64 (2H, t, J = 6.6 Hz), 2.55-2.74 (4H, m),2.38 (3H, s).  30a (CDCl3) δ: 8.82 (1H, s), 8.00 (1H, dd, J = 7.8, 1.5Hz), 518 7.67-7.59 (2H, m), 7.52-7.47 (2H, m), 7.41 (1H, dd, J = 7.8,1.0 Hz), 7.25 (1H, d, J = 8.8 Hz), 4.82 (2H, s), 4.30-4.18 (2H, m), 3.33(3H, s), 3.07-2.99 (4H, m), 2.78-2.51 (4H, m), 2.39 (3H, s), 1.21 (3H,t, J = 7.1 Hz).  31a (CDCl3) δ: 5.70 (1H, ddt, J = 17.1, 10.2, 5.9 Hz),5.12 (1H, dd, J = 10.2, 515 1.5 Hz), 4.99 (1H, dd, J = 17.1, 1.5 Hz),4.72 (2H, s), 4.40 (2H, d, J = 5.9 Hz), 4.33-4.26 (1H, m), 3.02-2.96(4H, m), 2.72-2.51 (4H, m), 2.38 (3H, s).  32a (CDCl3) δ: 8.83 (1H, s),8.02 (2H, d, J = 8.3 Hz), 7.58-7.50 (3H, 515 m), 7.22-7.18 (1H, m),7.17-7.08 (1H, m), 5.68 (1H, ddt, J = 17.1, 10.2, 5.9 Hz), 5.10 (1H, dd,J = 10.2, 1.5 Hz), 4.99 (1H, dd, J = 17.1, 1.5 Hz), 4.62 (2H, s), 4.45(2H, d, J = 5.9 Hz), 3.05-2.99 (4H, m), 2.73-2.55 (4H, m), 2.39 (3H, s). 33a (CD3OD) δ: 8.79 (1H, s), 7.99 (1H, s), 7.71 (1H, s), 7.56 (1H, d,460 J = 2.4 Hz), 7.38 (1H, dd, J = 8.4, 2.4 Hz), 6.99 (1H, d, J = 8.4Hz), 5.79 (1H, ddd, J = 17.2, 10.4, 5.6 Hz), 5.20 (1H, d, J = 10.4 Hz),5.07 (1H, d, J = 17.2 Hz), 4.43 (2H, d, J = 5.6 Hz), 3.99 (3H, s), 2.92(4H, m), 2.66 (4H, m), 2.40 (3H, s), 2.26 (3H, s).  34a (CD3OD) δ: 8.81(1H, s), 8.02 (1H, s), 7.83 (1H, d, J = 2.4 Hz), 476 7.71 (1H, s), 7.51(1H, dd, J = 8.4, 2.4 Hz), 7.10 (1H, d, 8.4 Hz), 5.79 (1H, ddd, J =17.2, 10.0, 5.2 Hz), 5.20 (1H, d, J = 10.0 Hz), 5.07 (1H, d, J = 17.2Hz), 4.71 (2H, s), 4.44 (2H, d, J = 5.2 Hz), 4.00 (3H, s), 2.98 (4H, m),2.91 (4H, m), 2.38 (3H, s).  35a (CDCl3) δ: 8.79 (1H, s), 8.12 (1H, d, J= 6.8 Hz), 8.06 (1H, brs), 500 7.63-7.50 (3H, m), 7.22-7.09 (1H, m),6.96 (1H, d, J = 8.3 Hz), 5.69 (1H, ddt, J = 17.1, 9.8, 5.9 Hz), 5.08(1H, d, J = 9.8 Hz), 4.97 (1H, d, J = 17.1 Hz), 4.41 (2H, d, J = 5.9Hz), 3.22-2.80 (8H, m), 2.67 (3H, s), 2.24 (3H, s).  36a (CDCl3) δ: 8.81(1H, s), 7.86-7.85 (1H, m), 7.80-7.76 (1H, 513 m), 7.61-7.56 (2H, m),7.47-7.38 (1H, m), 7.36-7.30 (2H, m), 6.97 (1H, d, J = 8.3 Hz),6.24-6.18 (1H, m), 5.69 (1H, ddt, J = 17.1, 10.2, 5.9 Hz), 5.10 (1H, dd,J = 10.2, 1.0 Hz), 4.98 (1H, dd, J = 17.1, 1.0 Hz), 4.39 (2H, d, J = 5.9Hz), 3.03 (3H, d, J = 4.9 Hz), 2.94-2.89 (4H, m), 2.64-2.53 (4H, m),2.37 (3H, s), 2.25 (3H, s).  37a (CDCl3) δ: 8.77 (1H, s), 7.17-7.49 (5H,m), 6.91 (1H, d, J = 8.1 Hz), 467 5.65-5.71 (1H, m), 5.12 (1H, d, J =10.2 Hz), 5.06 (1H, d, J = 17.0 Hz), 4.63 (2H, s), 4.40 (2H, d, J = 6.0Hz), 3.57 (3H, s), 1.30 (6H, s).  38a (CDCl3) δ: 8.84 (1H, s), 7.20-7.60(7H, m), 5.65-5.80 (1H, 451 m), 5.14 (1H, d, 10.3 Hz), 5.04 (1H, d, J =17.1 Hz), 4.42 (2H, d, J = 5.8 Hz), 3.67 (2H, s), 3.38 (2H, s), 1.17(6H, s).  39a (CDCl3) δ: 8.84 (1H, s), 7.24-7.71 (8H, m), 5.69-5.78 (1H,444 m), 5.15 (1H, d, J = 10.1 Hz), 5.04 (1H, d, J = 17.0 Hz), 4.43 (2H,d, J = 6.1 Hz), 3.96 (3H, s), 2.38 (3H, s).  40a (CDCl3) δ: 8.77 (1H,s), 7.18-7.50 (5H, m), 6.65 (1H, d, J = 7.5 Hz), 466 5.65-5.78 (1H, m),5.12 (1H, d, J = 10.5 Hz), 5.04 (1H, d, J = 16.8 Hz), 4.63 (2H, s),4.38-3.43 (2H, m), 3.27-3.30 (2H, m), 2.61-2.67 (2H, m), 2.31 (6H, s). 41a (CDCl3) δ: 8.74 (1H, s), 8.51 (1H, d, J = 4.4 Hz), 7.79-7.89 (2H,462 m), 7.19-7.70 (3H, m), 6.92 (1H, d, J = 7.3 Hz), 5.59-5.71 (1H, m),5.00 (1H, d, J = 10.2 Hz), 4.91 (1H, d, J = 16.8 Hz), 4.74 (2H, d, J =6.5 Hz), 4.64 (2H, s), 3.60 (2H, s), 1.32 (6H, s).  42a (CDCl3) δ: 8.82(1H, s), 7.46-7.43 (2H, m), 7.38-7.28 (2H, 460 m), 7.00 (1H, d, J = 8.8Hz), 6.48 (1H, d, J = 1.5 Hz), 5.73 (1H, ddt, J = 17.0, 10.2, 4.4 Hz),5.10-5.06 (2H, m), 4.60 (2H, d, J = 4.4 Hz), 3.95 (3H, s), 2.97-2.90(4H, m), 2.69-2.53 (4H, m), 2.38 (3H, s), 2.29 (3H, s).  43a (CDCl3) δ:8.80 (1H, s), 7.72 (1H, brs), 7.52-7.47 (1H, m), 522 7.46-7.41 (1H, m),7.41-7.36 (2H, m), 7.34-7.31 (2H, m), 7.06 (1H, d, J = 8.8 Hz), 3.87(2H, q, J = 7.0 Hz), 2.96-2.91 (4H, m), 2.66-2.53 (4H, m), 2.38 (3H, s),2.30 (3H, s), 1.07 (4H, t, J = 7.0 Hz).  44a (DMSO-d6) δ: 8.85 (1H, s),8.54 (1H, d, J = 2.5 Hz), 8.05 (1H, t, 443 J = 8.3 Hz), 7.88 (1H, d, J =8.3 Hz), 7.59-7.77 (1H, m), 7.38-7.43 (2H, m), 6.97 (1H, d, J = 8.3 Hz),5.61-5.72 (1H, m), 5.01 (1H, d, J = 10.2 Hz), 4.85 (1H, d, J = 17.0 Hz),4.59 (2H, m), 2.93-3.01 (4H, m), 3.78-3.86 (4H, m), 2.24 (3H, s).  45a(CDCl3) δ: 8.81 (1H, s), 7.80 (1H, s), 7.66 (1H, s), 7.56 (1H, br 524s), 7.53-7.46 (3H, m), 7.39-7.29 (3H, m), 6.90-6.81 (1H, m), 3.97 (3H,s), 3.90 (3H, q, J = 7.0 Hz), 2.92-2.84 (4H, m), 2.66-2.50 (4H, m), 2.38(3H, s), 2.19 (3H, s), 1.10 (4H, t, J = 7.0 Hz).  46a (DMSO-d6) δ: 10.15(1H, brs), 8.85 (1H, s), 8.05 (1H, dd, J = 8.0, 487 7.8 Hz), 7.76 (1H,d, J = 8.4 Hz), 7.66 (1H, brs), 7.45 (1H, d, J = 8.2 Hz), 7.41 (1H, d, J= 9.0 Hz), 6.99 (1H, d, J = 8.6 Hz), 5.75-5.60 (1H, m), 5.54 (1H, t, J =5.7 Hz), 5.01 (1H, d, J = 10.0 Hz), 4.87 (1H, d, J = 17.2 Hz), 4.60-4.58(4H, m), 2.81 (4H, brs), 2.45 (4H, brs), 2.24 (6H, s).  47a (CDCl3) δ:8.82 (1H, s), 8.54 (1H, d, J = 4.9 Hz), 7.93-7.84 (2H, 461 m), 7.55-7.48(1H, m), 7.33-7.24 (2H, m), 7.02 (1H, d, J = 8.8 Hz), 4.19 (2H, q, J =7.2 Hz), 2.97-2.91 (4H, m), 2.66-2.54 (4H, m), 2.38 (3H, s), 2.33 (3H,s), 1.07 (3H, t, J = 7.2 Hz).  48a (CDCl3) δ: 8.84 (1H, s), 8.55 (1H,dd, J = 4.4, 2.0 Hz), 7.94 (1H, t 445 d, J = 7.8, 2.0 Hz), 7.87 (1H, d,J = 8.8 Hz), 7.66-7.58 (1H, m), 7.38-7.32 (1H, m), 7.31-7.27 (1H, m),7.20 (1H, d, J = 8.8 Hz), 4.80 (2H, s), 4.19 (2H, q, J = 7.2 Hz),3.05-2.99 (4H, m), 2.73-2.53 (4H, m), 2.38 (3H, s), 1.08 (3H, t, J = 7.2Hz).  49a (CD3OD) δ: 8.80 (1H, s), 7.99 (1H, s), 7.82 (1H, d, J = 2.0Hz), 462 7.69 (1H, s), 7.57 (1H, dd, J = 8.8, 2.0 Hz), 7.11 (1h, J = 8.8Hz), 5.80 (1H, ddd, J = 17.2, 10.4, 5.2 Hz), 5.19 (1H, d, J = 10.4 Hz),5.10 (1H, d, J = 17.2 Hz), 4.72 (2H, s), 4.60 (2H, d, J = 5.2 Hz), 2.97(4H, m), 2.66 (4H, m), 2.39 (3H, s).  50a (CD3OD) δ: 9.38 (1H, s), 8.85(1H, s), 8.56 (1H, d, J = 11.2 Hz), 474 8.56 (1H, d, J = 11.2 Hz), 8.56(1H, d, J = 11.2 Hz), 7.83 (1H, J = 2.0 Hz), 7.53 (1H, dd, J = 8.8, 2.0Hz), 7.18 (1H, d, J = 8.8 Hz), 5.78 (1H, ddd, J = 16.8, 10, 6.8 Hz),5.09 (1H, d, J = 10 Hz), 5.00 (1H, d, J = 16.8 Hz), 4.79 (1H, d, J = 6.8Hz), 4.78 (2H, s), 3.02 (4H, m), 2.69 (4H, m), 2.41 (3H, s).  51a(CD3OD) δ: 8.78 (1H, s), 8.42 (1H, brs), 8.04 (1H, d, J = 7.3 Hz), 5247.73-7.66 (1H, m), 7.61 (1H, t, J = 7.8 Hz), 7.31 (1H, d, J = 7.8 Hz),7.15-7.06 (1H, m), 6.36-6.17 (1H, m), 5.77 (1H, ddt, J = 17.1, 10.2, 5.4Hz), 5.14 (1H, d, J = 10.2 Hz), 5.04 (1H, d, J = 17.1 Hz), 4.52 (2H, d,J = 5.4 Hz), 3.38-3.25 (4H, m), 2.97 (3H, s), 2.96-2.88 (4H, m), 2.08(3H, s).  52a (CDCl3) δ: 8.85 (1H, s), 7.81-7.53 (1H, m), 7.50 (1H, dd,J = 5.1, 520 3.2 Hz), 7.42 (1H, dd, J = 3.2, 1.2 Hz), 7.37-7.28 (1H, m),7.17 (1H, d, J = 8.8 Hz), 7.14 (1H, d, J = 5.4 Hz), 4.74 (2H, s), 4.40(2H, q, J = 8.1 Hz), 3.00 (4H, t, J = 4.6 Hz), 2.86-2.44 (4H, m), 2.38(3H, s).  53a (CDCl3) δ: 8.82 (1H, s), 8.36 (1H, d, J = 4.9 Hz), 7.68(1H, brs), 471 7.59-7.50 (1H, m), 7.22 (1H, brs), 7.06-7.03 (1H, m),7.03 (1H, d, J = 8.8 Hz), 5.68 (1H, ddt, J = 17.1, 10.2, 6.3 Hz), 5.02(1H, dd, J = 10.2, 1.5 Hz), 4.92 (1H, dd, J = 17.1, 1.5 Hz), 4.77 (2H,d, J = 6.3 Hz), 2.97-2.90 (4H, m), 2.69-2.52 (4H, m), 2.46 (3H, s), 2.38(3H, s), 2.30 (3H, s).  54a (CDCl3) δ: 8.84 (1H, s), 7.64-7.53 (1H, m),7.51 (1H, dd, J = 5.1, 502 3.2 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.37-7.28(1H, m), 7.22-7.14 (2H, m), 6.01 (1H, tt, J = 55.6, 4.4 Hz), 4.75 (2H,s), 4.12 (1H, td, J = 13.0, 4.2 Hz), 3.01 (4H, t, J = 4.6 Hz), 2.80-2.46(4H, m), 2.39 (3H, s).  55a (CDCl3) δ: 8.77 (1H, s), 7.62-7.47 (1H, m),7.45 (1H, dd, J = 5.1, 480 3.2 Hz), 7.39 (1H, dd, J = 3.4, 1.5 Hz),7.34-7.28 (1H, m), 7.21-7.14 (2H, m), 4.76 (2H, s), 4.32-4.25 (1H, m),3.00 (4H, t, J = 4.9 Hz), 2.78-2.47 (4H, m), 2.38 (3H, s), 1.39 (6H, d,J = 6.8 Hz).  56a (DMSO-d6) δ: 10.22 (1H, brs), 8.87 (1H, s), 8.56 (1H,dd, J = 4.9, 492 1.0 Hz), 8.10-8.06 (1H, m), 7.89 (1H, d, J = 8.3 Hz),7.69 (1H, brs), 7.49-7.37 (2H, m), 7.10 (1H, d, J = 8.8 Hz), 5.68 (1H,ddt, J = 17.1, 10.2, 5.9 Hz), 5.02 (1H, dd, J = 10.2, 1.5 Hz), 4.87 (1H,dd, J = 17.1, 1.5 Hz), 4.60 (2H, d, J = 5.9 Hz), 3.32 (2H, s), 3.26 (8H,s), 2.28 (3H, s).  57a (CDCl3) δ: 9.10 (1H, d, J = 2.3 Hz), 8.85 (1H,s), 8.39 (1H, dd, J = 8.6, 515 2.3 Hz), 8.11 (1H, d, J = 8.6 Hz),7.57-7.39 (2H, m), 7.31 (1H, dd, J = 8.6, 2.3 Hz), 7.05 (1H, d, J = 8.6Hz), 5.65 (1H, ddt, J = 17.0, 10.2, 6.3 Hz), 5.01 (1H, dd, J = 10.2, 1.2Hz), 4.92 (1H, dd, J = 17.0, 1.2 Hz), 4.86 (2H, d, J = 6.3 Hz), 3.99(3H, s), 2.98-2.93 (4H, m), 2.72-2.52 (4H, m), 2.38 (3H, s), 2.35 (3H,s).  58a (CDCl3) δ: 8.83 (1H, s), 8.54 (1H, d, J = 5.3 Hz), 7.90-7.83(2H, 548 m), 7.58 (2H, d, J = 8.8 Hz), 7.56 (1H, brs), 7.48 (2H, d, J =8.2 Hz), 5.69 (1H, ddt, J = 17.6, 10.4, 6.5 Hz), 5.02 (1H, d, J = 10.4Hz), 4.92 (1H, d, J = 17.6 Hz), 4.78 (2H, d, J = 6.5 Hz), 2.84-2.80 (2H,m), 2.55-2.49 (2H, m), 2.41 (3H, s), 2.25-2.22 (2H, m), 1.81-1.77 (2H,m).  59a (CD3OD) δ: 8.87 (1H, s), 8.57 (1H, d, J = 8.3 Hz), 8.06 (1H, t,J = 8.5 Hz), 428 7.93 (1H, d, J = 7.6 Hz), 7.68 (2H, d, J = 8.2 Hz),7.43 (1H, dd, J = 7.4, 4.9 Hz), 7.26 (2H, d, J = 8.6 Hz), 5.80-5.70 (1H,m), 5.08 (1H, d, J = 9.6 Hz), 4.96 (1H, d, J = 17.8 Hz), 4.74 (2H, d, J= 5.9 Hz), 3.52 (2H, d, J = 12.7 Hz), 3.14 (2H, dd, J = 13.3, 10.2 Hz),2.93-2.88 (1H, m), 2.10 (2H, d, J = 12.7 Hz), 1.98-1.87 (2H, m).  60a(CDCl3) δ: 8.81 (1H, s), 7.63-7.53 (5H, m), 7.43 (1H, d, J = 6.8 Hz),531 7.38-7.32 (1H, m), 7.16 (1H, d, J = 8.8 Hz), 4.75 (2H, s), 3.87 (2H,q, J = 7.0 Hz), 3.15 (3H, s), 3.05-2.95 (7H, m), 2.74-2.52 (4H, m), 2.38(3H, s), 1.07 (3H, t, J = 7.0 Hz).  61a (CDCl3) δ: 8.80 (1H, s),7.63-7.48 (4H, m), 7.46-7.33 (3H, 545 m), 6.98 (1H, d, J = 8.3 Hz), 3.87(2H, q, J = 7.0 Hz), 3.68 (2H, t, J = 5.4 Hz), 3.14 (3H, s), 2.98 (3H,s), 2.96-2.91 (4H, m), 2.76-2.67 (4H, m), 2.65 (2H, t, J = 5.4 Hz), 2.29(3H, s), 1.07 (3H, t, J = 7.0 Hz).  62a (CDCl3) δ: 8.85 (1H, s), 8.58(1H, d, J = 1.5 Hz), 7.86 (1H, dt, J = 4.5, 523 1.5 Hz), 7.65 (1H, d, J= 4.5 Hz), 6.92-7.29 (8H, m), 5.36 (2H, s), 4.75 (2H, s), 3.00-3.03 (4H,m), 2.52-2.79 (4H, m), 2.40 (3H, s).  63a (CDCl3) δ: 9.17 (1H, s),8.84-8.87 (3H, m), 7.55-7.80 (3H, bs), 524 7.00-7.26 (5H, m), 4.99 (2H,s), 4.77 (2H, m), 2.98-3.01 (4H, m), 2.63 (4H, bs), 2.37 (3H, s).  64a(CDCl3) δ: 8.89 (1H, s), 8.55 (1H, d, J = 5.1 Hz), 8.14-7.85 (3H, 487m), 7.63-7.16 (4H, m), 5.71 (1H, ddt, J = 17.1, 10.2, 5.9 Hz), 5.03 (1H,d, J = 10.2 Hz), 4.92 (1H, d, J = 17.1 Hz), 4.72 (2H, d, J = 5.9 Hz),3.26 (0.75H, t, J = 7.0 Hz), 3.13 (1.25H, s), 2.87 (1.75H, s), 2.62(1.25H, t, J = 7.0 Hz), 2.34 (3H, s), 2.32 (3H, s), 2.05 (3H, s),2.04-1.90 (2H, m)  65a (CDCl3) δ: 8.83 (1H, s), 8.53 (1H, d, J = 4.9Hz), 7.93-7.31 (6H, 460 m), 5.69 (1H, ddt, J = 17.1, 10.2, 5.9 Hz), 5.02(1H, d, J = 10.2 Hz), 4.92 (1H, d, J = 17.1 Hz), 4.80 (2H, d, J = 5.9Hz), 3.88 (2H, t, J = 6.0 Hz), 2.76 (2H, t, J = 6.0 Hz), 2.38 (6H, s),2.30 (6H, s).  66a (CDCl3) δ: 8.83 (1H, s), 7.74 (1H, brs), 7.52 (1H,brs), 7.44 (2H, 487 brs), 7.27 (2H, brs), 7.01 (1H, d, J = 8.5 Hz), 6.70(1H, brs), 5.78-5.65 (1H, m), 5.06-4.90 (2H, m), 4.81 (2H, brs), 3.94(3H, s), 2.94 (4H, brs), 2.61 (4H, brs), 2.39 (3H, s), 2.32 (3H, s). 67a (CDCl3) δ: 8.88 (1H, s), 7.82 (1H, dd, J = 8.2, 7.8 Hz), 7.64 (1H,503 brs), 7.47 (1H, brs), 7.43 (1H, d, J = 7.4 Hz), 7.41 (1H, brs), 7.24(1H, d, J = 8.2 Hz), 5.80-5.70 (1H, m), 5.08 (1H, d, J = 9.2 Hz), 5.00(1H, d, J = 18.0 Hz), 4.85-4.81 (4H, m), 3.97 (3H, s), 3.00 (3H, brs),2.67 (4H, brs), 2.43 (3H, s).  68a (CD3OD) δ: 8.79 (1H, s), 7.89 (1H, t,J = 7.8 Hz), 7.66 (1H, d, J = 7.9 Hz), 471 7.55 (1H, brs), 7.39 (1H, d,J = 8.8 Hz), 7.25 (1H, d, J = 7.8 Hz), 7.00 (1H, d, J = 8.6 Hz), 5.72(1H, ddt, J = 17.2, 10.8, 6.1 Hz), 5.04 (1H, d, J = 10.8 Hz), 4.92 (1H,d, J = 17.2 Hz), 4.69 (2H, d, J = 6.1 Hz), 2.91 (4H, brs), 2.62 (4H,brs), 2.56 (3H, s), 2.36 (3H, s), 2.27 (3H, s).  69a (CDCl3) δ: 8.84(1H, s), 7.92 (1H, d, J = 8.3 Hz), 7.68 (1H, t, J = 7.8 Hz), 535 7.43(1H, brs), 7.40 (1H, d, J = 6.8 Hz), 7.36 (1H, dd, J = 8.0, 1.2 Hz),7.05 (1H, d, J = 8.8 Hz), 5.69 (1H, ddt, J = 17.1, 10.2, 6.3 Hz), 5.04(1H, dd, J = 10.2, 1.5 Hz), 4.99 (1H, dd, J = 17.1, 1.5 Hz), 4.81 (2H,d, J = 6.3 Hz), 3.01 (4H, brs), 2.71 (4H, br s), 2.46 (3H, s), 2.32 (3H,s), 1.13 (1H, d, J = 6.3 Hz), 0.00 (6H, t, J = 3.4 Hz).  70a (CD3OD) δ:8.80 (1H, s), 8.12 (1H, dd, J = 15.6, 7.6 Hz), 7.87 (1H, 475 d, J = 7.8Hz), 7.56 (1H, brs), 7.40 (1H, d, J = 11.2 Hz), 7.05-7.01 (2H, m), 5.73(1H, ddt, J = 16.2, 10.2, 6.3 Hz), 5.06 (1H, d, J = 10.2 Hz), 4.98 (1H,d, J = 16.2 Hz), 4.74 (2H, d, J = 6.3 Hz), 2.93 (4H, brs), 2.63 (4H,brs), 2.36 (3H, s), 2.30 (3H, s).  71a (CDCl3) δ: 8.85 (1H, s), 7.99(1H, dd, J = 15.9, 7.8 Hz), 7.79 (1H, 491 d, J = 7.6 Hz), 7.59 (1H,brs), 7.52 (1H, brs), 7.37 (1H, brs), 7.22 (1H, d, J = 8.2 Hz), 6.87(1H, dd, J = 5.7, 2.4 Hz), 5.75-5.60 (1H, m), 5.02 (1H, d, J = 10.2 Hz),4.98 (1H, d, J = 17.2 Hz), 4.80 (4H, brs), 3.04 (4H, brs), 2.64 (4H,brs), 2.40 (3H, s).  72a (CDCl3) δ: 8.85 (1H, s), 8.53 (1H, d, J = 3.1Hz), 7.83-7.95 (2H, 474 m), 7.17-7.80 (4H,), 5.62-5.73 (1H, m), 5.60(1H, bs), 5.02 (1H, d, J = 10.0 Hz), 4.91 (1H, d, J = 17.2 Hz),4.76-4.81 (4H, m), 3.91 (1H, bs), 3.12-3.20 (2H, m), 2.79-2.87 (2H, m),2.06-2.12 (2H, m), 1.73-1.86 (2H, m).  73a (DMSO-d6) δ: 8.83 (1H, s),8.03-7.99 (1H, m), 7.96 (1H, d, J = 6.8 Hz), 487 7.73-7.65 (2H, m),7.52-7.45 (2H, m), 6.93 (1H, d, J = 9.3 Hz), 5.66 (1H, ddt, J = 17.1,10.2, 8.3 Hz), 5.07 (1H, dd, J = 10.2, 1.5 Hz), 4.92 (1H, dd, J = 17.1,1.5 Hz), 4.29 (2H, brs), 3.73-3.69 (4H, m), 2.79-2.74 (4H, m), 2.16 (3H,s).  74a (CDCl3) δ: 8.83 (1H, s), 7.62-7.49 (5H, m), 7.43 (1H, dd, J =7.3, 543 1.0 Hz), 7.36-7.29 (1H, m), 7.15 (1H, d, J = 8.8 Hz), 5.68 (1H,ddt, J = 17.1, 10.2, 6.3 Hz), 5.10 (1H, d, J = 10.2 Hz), 4.98 (1H, d, J= 17.1 Hz), 4.73 (2H, s), 4.40 (2H, d, J = 6.3 Hz), 3.14 (3H, s),3.04-2.96 (7H, m), 2.72-2.54 (4H, m), 2.38 (3H, s).  75a (CDCl3) δ: 8.84(1H, s), 8.58 (1H, dd, J = 2.3, 0.7 Hz), 8.05 (1H, 528 d, J = 8.5 Hz),7.94 (1H, dd, J = 8.5, 2.3 Hz), 7.63-7.40 (2H, m), 7.30 (1H, dd, J =8.6, 2.3 Hz), 7.03 (1H, d, J = 8.6 Hz), 5.67 (1H, ddt, J = 16.8, 10.0,6.6 Hz), 5.03 (1H, dd, J = 10.2, 1.2 Hz), 4.95 (1H, dd, J = 16.8, 1.2Hz), 4.82 (2H, d, J = 6.6 Hz), 3.17 (3H, brs), 3.08 (3H, brs), 2.99-2.89(4H, m), 2.72-2.51 (4H, m), 2.39 (3H, s), 2.34 (3H, s).  76a (CD3OD) δ:8.78 (1H, s), 8.07 (1H, brs), 7.91 (1H, brs), 486 7.88-7.83 (1H, m),7.61-7.56 (2H, m), 7.52-7.43 (2H, m), 7.42-7.36 (1H, m), 6.88 (1H, d, J= 8.8 Hz), 5.61 (1H, ddt, J = 17.3, 10.5, 6.3 Hz), 5.02 (1H, dd, J =10.5, 1.2 Hz), 4.86 (1H, dd, J = 17.3, 1.2 Hz), 4.24 (2H, brs),3.67-3.62 (4H, m), 2.72-2.68 (4H, m), 2.11 (3H, s).  77a (CDCl3) δ: 8.84(1H, s), 8.55 (1H, d, J = 5.1 Hz), 7.96-7.94 (1H, 528 m), 7.60-7.44 (2H,m), 7.19 (1H, dd, J = 5.1, 1.2 Hz), 7.05 (1H, d, J = 8.3 Hz), 5.69 (1H,ddt, J = 17.1, 10.0, 6.3 Hz), 5.04 (1H, dd, J = 10.0, 1.2 Hz), 4.96 (1H,dd, J = 17.1, 1.0 Hz), 4.80 (2H, d, J = 6.3 Hz), 3.15 (3H, s), 2.99-2.95(4H, m), 2.81 (3H, s), 2.68-2.57 (4H, m), 2.39 (3H, s), 2.31 (3H, s). 78a (CDCl3) δ: 8.85 (1H, s), 8.56 (1H, d, J = 5.4 Hz), 7.95 (1H, s),544 7.80-7.66 (1H, m), 7.52-7.46 (2H, m), 7.23-7.17 (2H, m), 5.68 (1H,ddt, J = 17.1, 10.2, 6.3 Hz), 5.03 (1H, d, J = 10.2 Hz), 4.94 (1H, d, J= 17.1 Hz), 4.79 (2H, d, J = 6.3 Hz), 4.77 (2H, s), 3.16 (3H, s),3.04-2.99 (4H, m), 2.90 (3H, s), 2.71-2.55 (4H, m), 2.38 (3H, s).  79a(CDCl3) δ: 8.79 (1H, s), 8.56-8.54 (1H, m), 7.87 (1H, td, J = 7.8, 4712.0 Hz), 7.74 (1H, d, J = 7.8 Hz), 7.52-7.37 (2H, m), 7.30-7.26 (1H, m),7.00 (1H, d, J = 8.8 Hz), 4.71-4.69 (1H, m), 2.94 (4H, t, J = 4.6 Hz),2.69-2.45 (6H, m), 2.39 (3H, s), 2.32 (3H, s), 2.23-2.15 (2H, m),1.74-1.56 (2H, m), 1.26 (3H, ddd, J = 36.2, 20.6, 16.5 Hz).  80a (CDCl3)δ: 8.83 (1H, s), 8.37 (1H, d, J = 2.7 Hz), 7.91-7.85 (1H, 475 m),7.64-7.35 (3H, m), 7.33-7.22 (1H, m), 7.02 (1H, d, J = 8.85 Hz), 5.67(1H, ddt, J = 16.8, 10.2, 6.5 Hz), 5.03 (1H, d, J = 10.2 Hz), 4.93 (1H,d, J = 16.8 Hz), 4.73 (2H, d, J = 6.5 Hz), 2.98-2.92 (4H, m), 2.72-2.50(4H, m), 2.39 (3H, s), 2.32 (3H, s).  81a (CDCl3) δ: 8.81 (1H, s), 8.51(1H, d, J = 3.2 Hz), 7.79-7.92 (2H, 446 m), 7.18-7.70 (3H, m), 6.86 (1H,d, J = 8.5 Hz), 5.63-5.75 (1H, m), 5.01 (1H, d, J = 10.2 Hz), 4.91 (1H,d, J = 17.1 Hz), 4.78 (2H, d, J = 6.0 Hz), 3.59 (2H, s), 2.22 (3H, s),1.30 (9H, s).  82a (CD3OD) δ: 8.88 (1H, s), 8.59-8.57 (1H, m), 8.06 (1H,t, J = 8.2 Hz), 440 7.95 (1H, d, J = 8.2 Hz), 7.70 (1H, brs), 7.50-7.42(2H, m), 7.10 (1H, d, J = 8.6 Hz), 5.76 (1H, ddt, J = 16.8, 10.8, 6.3Hz), 5.09 (1H, d, J = 10.8 Hz), 4.96 (1H, d, J = 16.8 Hz), 4.75 (2H, d,J = 6.3 Hz), 3.86 (2H, brs), 3.49 (2H, t, J = 6.0 Hz), 2.64 (2H, brs),2.36 (3H, s).  83a (CD3OD) δ: 8.87 (1H, s), 8.57-8.56 (1H, m), 8.08-8.04(1H, 442 m), 7.95 (1H, d, J = 8.2 Hz), 7.64 (1H, brs), 7.46-7.42 (2H,m), 7.19 (1H, d, J = 8.2 Hz), 5.76 (1H, ddt, J = 18.6, 10.2, 6.1 Hz),5.08 (1H, d, J = 10.2 Hz), 4.97 (1H, d, J = 18.6 Hz), 4.75 (2H, d, J =6.1 Hz), 3.49-3.45 (2H, m), 3.17-3.10 (2H, m), 2.40 (3H, s), 2.01-1.85(4H, m).  84a (CDCl3) δ: 8.83 (1H, s), 7.64 (1H, brs), 7.61 (1H, dd, J =8.2, 7.8 Hz), 544 7.42-7.34 (2H, m), 7.26 (1H, d, J = 9.0 Hz), 6.98 (1H,d, J = 8.0 Hz), 6.41 (1H, d, J = 8.8 Hz), 5.77-5.63 (1H, m), 5.04 (1H,d, J = 10.0 Hz), 4.97 (1H, d, J = 15.3 Hz), 4.86-4.70 (5H, m), 3.10-2.91(4H, brs), 2.85 (3H, s), 2.76-2.60 (4H, brs), 2.40 (3H, s), 1.16 (6H, d,J = 6.9 Hz).  85a (CDCl3) δ: 8.85 (1H, s), 8.54 (1H, d, J = 4.9 Hz),7.90-7.84 (2H, 521 m), 7.76-7.45 (2H, m), 7.36 (1H, dd, J = 8.5, 2.4Hz), 7.30-7.24 (1H, m), 7.00 (1H, d, J = 8.5 Hz), 5.69 (1H, ddt, J =16.8, 10.2, 6.5 Hz), 5.02 (1H, d, J = 10.2 Hz), 4.92 (1H, d, J = 16.8Hz), 4.78 (2H, d, J = 6.5 Hz), 3.43-3.37 (4H, m), 3.03-2.98 (4H, m),2.86 (3H, s), 2.33 (3H, s).  86a (CDCl3) δ: 8.83 (1H, s), 8.52 (1H, d, J= 2.8 Hz), 7.01-7.80 (4H, 497 m), 5.63-5.74 (1H, m), 5.02 (1H, d, J =9.9 Hz), 4.91 (1H, d, J = 17.5 Hz), 4.79 (2H, d, J = 6.0 Hz), 2.96-2.98(4H, m), 2.63 (4H, bs), 2.34 (3H, s), 2.32-2.382H, m), 0.89-0.99 (1H,m), 0.54-0.59 (2H, m), 0.15-0.192H, m).  87a (CDCl3) δ: 8.78 (1H, s),8.55 (1H, d, J = 3.9 Hz), 7.89 (2H, dt, J = 3.9, 457 8.3 Hz), 7.81 (2H,d, J = 8.3 Hz), 7.49 (1H, brs), 7.30-7.25 (3H, m), 7.00 (1H, d, J = 8.8Hz), 3.33 (1H, s), 2.94 (4H, t, J = 4.9 Hz), 2.62 (4H, brs), 2.39 (3H,s), 2.31 (3H, s), 0.95-0.89 (4H, m).  88a (CDCl3) δ: 8.80 (1H, s), 8.52(1H, dt, J = 4.8, 1.4 Hz), 7.89 (1H, 430 d, J = 7.6 Hz), 7.84 (1H, dt, J= 1.7, 7.6 Hz), 7.57-7.14 (4H, m), 6.48 (1H, d, J = 8.5 Hz), 5.68 (1H,ddt, J = 16.8, 10.2, 6.5 Hz), 5.01 (1H, dd, J = 10.2, 1.2 Hz), 4.92 (1H,dd, J = 16.8, 1.2 Hz), 4.78 (2H, d, J = 6.5 Hz), 4.76-4.68 (1H, m),4.24-4.19 (2H, m), 3.71-3.65 (2H, m), 2.30-2.18 (1H, m), 2.22 (3H, s). 89a (CDCl3) δ: 8.83 (1H, s), 7.47 (1H, s), 6.96-7.36 (9H, m), 510 4.96(2H, s), 3.92 (3H, s), 2.92 (4H, s), 2.55-2.72 (4H, bs), 2.39 (3H, s),2.26 (3H, s).  90a (CDCl3) δ: 8.80 (1H, s), 7.46 (1H, brs), 7.32 (1H,dd, J = 8.8, 2.0 Hz), 471 7.27 (1H, t, J = 8.0 Hz), 6.98 (1H, d, J = 8.8Hz), 6.81 (1H, d, J = 8.0 Hz), 6.74 (1H, s), 6.68 (1H, dd, J = 8.3, 2.0Hz), 5.71 (1H, ddt, J = 17.1, 10.2, 6.3 Hz), 5.11 (1H, dd, J = 10.2, 1.0Hz), 5.02 (1H, dd, J = 17.1, 1.0 Hz), 4.40 (2H, d, J = 6.3 Hz), 3.84(2H, s), 2.95-2.89 (4H, m), 2.66-2.52 (4H, m), 2.37 (3H, s), 2.28 (3H,s).  91a (CDCl3) δ: 8.82 (1H, s), 7.57-7.49 (1H, m), 7.47 (1H, t, J =7.8 Hz), 500 7.43-7.32 (5H, m), 6.95 (1H, d, J = 8.8 Hz), 5.70 (1H, ddt,J = 17.1, 10.0, 5.9 Hz), 5.09 (1H, dd, J = 10.0, 1.5 Hz), 4.97 (1H, dd,J = 17.1, 1.5 Hz), 4.39 (2H, d, J = 5.9 Hz), 3.87-3.82 (4H, m), 3.51(2H, s), 2.89-2.85 (4H, m), 2.28 (9H, s).  92a (CDCl3) δ: 8.85 (1H, s),8.76 (1H, dd, J = 2.2, 0.7 Hz), 8.25 (1H, 482 dd, J = 8.8, 0.7 Hz), 8.00(1H, d, J = 8.8 Hz), 7.69-7.22 (3H, m), 7.06 (1H, d, J = 8.5 Hz), 5.64(1H, ddt, J = 16.8, 10.2, 6.6 Hz), 5.03 (1H, dd, J = 10.2, 1.0 Hz), 4.95(1H, dd, J = 16.8, 1.0 Hz), 4.85 (2H, d, J = 6.6 Hz), 3.00-2.94 (4H, m),2.75-2.50 (4H, m), 2.40 (3H, s), 2.35 (3H, s).  93a (CDCl3) δ: 8.81 (1H,s), 7.47 (1H, t, J = 8.0 Hz), 7.43-7.32 (6H, 513 m), 6.96 (1H, d, J =8.0 Hz), 5.69 (1H, ddt, J = 17.1, 10.2, 5.9 Hz), 5.09 (1H, dd, J = 10.2,1.0 Hz), 4.96 (1H, dd, J = 17.1, 1.0 Hz), 4.39 (2H, d, J = 5.9 Hz), 3.50(2H, s), 2.94-2.90 (4H, m), 2.65-2.55 (4H, m), 2.38 (3H, s), 2.27 (6H,s), 2.17 (3H, s).  94a (CDCl3) δ: 8.81 (1H, s), 7.73-7.62 (1H, m),7.50-7.34 (6H, 486 m), 6.95 (1H, d, J = 8.8 Hz), 5.69 (1H, ddt, J =17.1, 10.2, 5.9 Hz), 5.09 (1H, dd, J = 10.2, 1.0 Hz), 4.98 (1H, dd, J =17.1, 1.0 Hz), 4.39 (2H, d, J = 5.9 Hz), 3.88 (2H, s), 3.86-3.82 (4H,m), 2.89-2.85 (4H, m), 2.50 (3H, s), 2.28 (3H, s).  95a (CDCl3) δ: 8.81(1H, s), 7.49 (1H, t, J = 8.8 Hz), 7.40-7.23 (6H, 549 m), 6.99 (1H, d, J= 8.8 Hz), 5.69 (1H, ddt, J = 17.1, 10.2, 6.3 Hz), 5.10 (1H, dd, J =10.2, 1.0 Hz), 5.00 (1H, dd, J = 17.1, 1.0 Hz), 4.41 (2H, d, J = 6.3Hz), 3.04 (3H, s), 2.94-2.89 (4H, m), 2.66-2.55 (4H, m), 2.37 (3H, s),2.27 (3H, s).  96a (CDCl3) δ: 8.91 (1H, s), 8.19 (1H, d, J = 8.0 Hz),8.09 (1H, dd, J = 8.0, 515 7.6 Hz), 8.01 (1H, d, J = 7.5 Hz), 7.61 (1H,brs), 7.39 (1H, brs), 7.25 (1H, d, J = 8.8 Hz), 5.76-5.68 (1H, m), 5.06(1H, d, J = 10.4 Hz), 4.94-4.82 (3H, m), 4.82 (2H, s), 3.07 (4H, t, J =4.9 Hz), 2.75 (3H, s), 2.72 (4H, brs), 2.43 (3H, s).  97a (CDCl3) δ:8.86 (1H, s), 8.53 (1H, d, J = 4.7 Hz), 7.86 (1H, d, J = 4.3 Hz), 4707.72 (1H, brs), 7.51 (2H, d, J = 8.2 Hz), 7.25 (2H, dd, J = 4.9, 4.4Hz), 7.19 (2H, d, J = 8.4 Hz), 5.69 (1H, ddt, J = 16.8, 10.4, 5.8 Hz),5.02 (1H, d, J = 10.4 Hz), 4.92 (1H, d, J = 16.8 Hz), 4.79 (2H, d, J =5.8 Hz), 3.06 (2H, d, J = 11.6 Hz), 2.82 (1H, septet, J = 6.5 Hz),2.50-2.26 (1H, m), 1.85-1.81 (4H, m), 1.12 (6H, d, J = 6.5 Hz).  98a(CD3OD) δ: 8.91 (1H, s), 8.57 (1H, d, J = 5.2 Hz), 8.12 (1H, dd, J =8.8, 439 8.4H), 8.01 (1H, s), 7.94 (1H, d, J = 8.4 Hz), 7.98 (1H, d, J =8.4 Hz), 7.88 (2H, d, J = 9.2 Hz), 7.51 (2H, d, J = 9.2 Hz), 7.44 (1H,dd, J = 8.8, 5.2 Hz), 7.30 (1H, s), 5.76 (1H, ddd, J = 17.2, 10.4, 6.0Hz), 5.09 (1H, d, J = 10.4 Hz), 4.97 (1H, d, J = 17.2 Hz), 4.76 (2H, d,J = 6.0 Hz), 2.29 (3H, s).  99a (CDCl3) δ: 8.82 (1H, s), 8.52 (1H, td, J= 3.2, 1.7 Hz), 482 7.89-7.81 (2H, m), 7.72-7.32 (2H, m), 7.28-7.17 (2H,m), 6.55 (1H, d, J = 8.8 Hz), 5.68 (1H, ddt, J = 17.0, 10.3, 6.3 Hz),5.01 (1H, dd, J = 10.3, 1.3 Hz), 4.92 (1H, dd, J = 17.0, 1.3 Hz),4.81-4.71 (3H, m), 3.89-3.83 (2H, m), 3.12-3.06 (2H, m), 2.42 (1H, ttt,J = 6.1, 6.1, 6.1 Hz), 2.24 (3H, s), 0.99 (6H, d, J = 6.1 Hz). 100a(CDCl3) δ: 8.84 (1H, s), 8.54 (1H, d, J = 4.6 Hz), 7.82-7.92 (2H, 499m), 7.18-7.78 (4H, m), 5.63-5.72 (1H, m), 5.02 (1H, d, J = 10.2 Hz),4.91 (1H, d, J = 17.3 Hz), 4.77-4.80 (4H, m), 2.98 (4H, bs), 2.83 (4H,bs), 1.62 (1H, bs), 0.43-0.59 (4H, m). 101a (CDCl3) δ: 8.82 (1H, s),7.50 (1H, t, J = 8.3 Hz), 7.41 (1H, s), 536 7.37 (1H, dd, J = 8.8, 2.4Hz), 7.34-7.28 (3H, m), 7.00 (1H, d, J = 8.3 Hz), 5.70 (1H, ddt, J =17.1, 10.0, 6.3 Hz), 5.11 (1H, dd, J = 10.0, 1.0 Hz), 5.00 (1H, dd, J =17.1, 1.0 Hz), 4.42 (2H, d, J = 6.3 Hz), 3.87-3.83 (4H, m), 3.05 (3H,s), 2.91-2.87 (4H, m), 2.31 (3H, s). 102a (CDCl3) δ: 8.84 (1H, s), 8.54(1H, d, J = 4.9 Hz), 7.90-7.87 (2H, 431 m), 7.50 (1H, brs), 7.40 (1H,brs), 7.31 (1H, d, J = 9.0 Hz), 7.03 (1H, d, J = 8.6 Hz), 3.56 (3H, s),2.96 (4H, t, J = 4.5 Hz), 2.62 (4H, brs), 2.39 (3H, s), 2.33 (3H, s).103a (CD3OD) δ: 8.80 (1H, s), 7.69 (1H, s), 7.53 (2H, m), 7.32 (1H, 598s), 7.01 (1H, d, J = 8.8 Hz), 5.77 (1H, ddd, J = 16.8, 10.4, 10.0 Hz),5.16 (1H, d, J = 10.4 Hz), 5.06 (1H, d, J = 16.8 Hz), 4.48 (2H, d, J =10.0 Hz), 3.16 (6H, s), 3.01 (6H, s), 2.95 (4H, m), 2.66 (4H, m), 2.39(3H, s), 2.27 (3H, s). 104a (CDCl3) δ: 8.81 (1H, s), 7.47 (2H, t, J =7.8 Hz), 7.43-7.29 (4H, 539 m), 6.94 (1H, d, J = 8.8 Hz), 5.75-5.64 (1H,m), 5.09 (1H, dd, J = 10.2, 1.0 Hz), 4.96 (1H, dd, J = 17.1, 1.0 Hz),4.39 (2H, d, J = 6.3 Hz), 3.51 (2H, s), 2.86 (4H, t, J = 4.4 Hz),2.82-2.74 (4H, m), 2.28 (6H, s), 1.74-1.66 (1H, m), 0.52-0.43 (4H, m).105a (CDCl3) δ: 8.82 (1H, s), 7.66-7.55 (1H, m), 7.46 (2H, t, J = 7.8Hz), 555 7.45-7.40 (1H, m), 7.32 (2H, t, J = 9.0 Hz), 7.11 (1H, d, J =8.3 Hz), 5.75-5.64 (1H, m), 5.10 (1H, dd, J = 10.2, 1.0 Hz), 4.97 (1H,dd, J = 17.1, 1.5 Hz), 4.74 (2H, s), 4.39 (2H, d, J = 5.9 Hz), 3.51 (2H,s), 2.93 (4H, t, J = 4.6 Hz), 2.88-2.69 (4H, m), 2.25 (6H, s), 1.71-1.68(1H, m), 0.53-0.42 (4H, m). 106a (CDCl3) δ: 8.83 (1H, s), 7.61-7.33 (6H,m), 6.99 (1H, d, J = 8.3 Hz), 548 5.75-5.64 (1H, m), 5.10 (1H, d, J =10.2 Hz), 4.96 (1H, d, J = 17.1 Hz), 4.39 (2H, d, J = 5.9 Hz), 3.51 (2H,s), 3.38 (4H, t, J = 5.1 Hz), 3.20 (4H, t, J = 5.1 Hz), 2.27 (6H, s).107a (CDCl3) δ: 8.80 (1H, s), 7.48-7.33 (6H, m), 6.87 (2H, d, J = 8.8Hz), 499 5.80-5.60 (1H, m), 5.09 (1H, dd, J = 10.2, 1.0 Hz), 4.97 (1H,dd, J = 17.1, 1.5 Hz), 4.38 (1H, d, J = 5.9 Hz), 3.51 (2H, s), 3.18 (4H,t, J = 4.9 Hz), 2.60 (4H, t, J = 4.9 Hz), 2.37 (3H, s), 2.28 (6H, s).108a (CDCl3) δ: 8.83 (1H, s), 7.86 (1H, t, J = 6.0 Hz), 7.75 (1H, d, J =8.2 Hz), 473 7.46 (2H, d, J = 8.6 Hz), 7.40 (1H, brs), 7.22 (1H, d, J =7.6 Hz), 6.92 (2H, d, J = 9.0 Hz), 5.71 (1H, ddt, J = 16.8, 10.2, 5.9Hz), 5.06 (1H, d, J = 10.2 Hz), 4.96 (1H, d, J = 16.8 Hz), 4.81 (2H, d,J = 5.5 Hz), 4.71 (1H, d, J = 5.9 Hz), 3.23 (4H, brs), 3.14 (1H, t, J =5.5 Hz), 2.64 (4H, brs), 2.40 (3H, s). 109a (CDCl3) δ: 8.80 (1H, s),7.39-7.58 (6H, m), 6.89 (2H, d, J = 8.1 Hz), 543 5.62-5.77 (1H, m), 5.10(1H, d, J = 9.9 Hz), 4.99 (1H, d, J = 17.0 Hz), 4.40 (2H, d, J = 5.8Hz), 3.69 (2H, t, J = 5.9 Hz), 3.190-03.28 (4H, m), 3.14 (3H, s), 2.95(3H, s), 3.68-3.74 (4H, m), 2.65 (2H, t, J = 5.9 Hz). 110a (CDCl3) δ:8.80 (1H, s), 7.26-7.68 (6H, m), 6.80 (1H, d, J = 8.2 Hz), 568 5.65-5.75(1H, m), 5.09 (1H, d, J = 10.0 Hz), 4.99 (1H, d, J = 17.2 Hz), 4.39 (2H,d, J = 5.9 Hz), 4.31 (1H, bs), 3.12 (3H, s), 2.85-2.99 (5H, m), 2.51(2H, bs), 2.21 (3H, s), 1.92-2.01 (2H, m), 1.77-1.89 (2H, m), 1.62-1.70(1H, m), 0.42-0.53 (4H, m). 111a (CD3OD) δ: 8.81 (1H, s), 8.55 (1H, d, J= 4.8 Hz), 8.02 (1H, dd, J = 8.0, 444 8.0 Hz), 7.91 (1H, d, J = 8.0 Hz),7.56 (1H, s), 7.42 (1H, dd, 8.0, 4.8 Hz), 7.34 (1H, d, J = 8.8 Hz), 6.60(1H, d, J = 8.8 Hz), 5.75 (1H, ddd, J = 16.8, 10.4, 6.0 Hz), 5.07 (1H,d, J = 10.4 Hz), 4.95 (1H, d, J = 16.8 Hz), 4.81 (1H, m), 4.74 (2H, d, J= 6.0 Hz), 3.87 (1H, m), 3.28 (1H, m), 2.67 (3H, s), 2.49 (3H, s). 112a(CD3OD) δ: 8.80 (1H, s), 8.55 (1H, d, J = 4.8 Hz), 8.03 (1H, dd, 8.0,458 8.0 Hz), 7.91 (1H, d, J = 8.0 Hz), 7.56 (1H, s), 7.41 (1H, d, J =8.0 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.60 (1H, d, J = 8.4 Hz), 5.73 (1H,ddd, J = 17.2, 10.0, 6.4 Hz), 5.65 (1H, d, J = 10.0 Hz), 4.94 (1H, d, J= 17.2 Hz), 4.83 (1H, m), 4.73 (2H, d, J = 6.4 Hz), 3.83 (1H, m), 3.22(1H, m), 2.63 (2H, q, J = 7.2 Hz), 2.39 (3H, s), 1.05 (3H, t, J = 7.2Hz). 113a (CD3OD) δ: 8.80 (1H, s), 8.50 (1H, d, J = 4.8 Hz), 8.03 (1H,dd, J = 8.0, 474 8.0 Hz), 7.91 (1H, d, J = 8.0 Hz), 7.56 (1H, s), 7.41(1H, dd, J = 8.0, 4.8 Hz), 7.33 (1H, d, J = 8.4 Hz), 6.59 (1H, d, J =8.4 Hz), 5.74 (1H, ddd, J = 16.8, 10.0, 6.0 Hz), 5.07 (1H, d, J = 10.0Hz), 4.95 (1H, d, J = 16.8 Hz), 4.83 (1H, m), 4.73 (1H, d, J = 6.0 Hz),3.91 (1H, m), 3.63 (1H, t, J = 5.6 Hz), 3.29 (1H, m), 2.74 (1H, t, J =5.6 Hz), 2.04 (3H, s). 114a (CDCl3) δ: 8.82 (1H, s), 8.54 (1H, dd, J =4.9, 1.5 Hz), 485 7.91-7.84 (2H, m), 7.67-7.44 (1H, m), 7.33-7.23 (2H,m), 7.02 (1H, d, J = 8.3 Hz), 4.21 (2H, d, J = 7.3 Hz), 2.95 (4H, t, J =4.9 Hz), 2.72-2.50 (4H, m), 2.49-2.40 (1H, m), 2.39 (3H, s), 2.33 (3H,s), 1.90-1.69 (4H, m), 1.65-1.53 (2H, m). 115a (CDCl3) δ: 8.78 (1H, s),8.54 (1H, d, J = 4.9 Hz), 7.87-7.82 (1H, 521 m), 7.81-7.75 (1H, m),7.67-7.41 (2H, m), 7.40-7.10 (3H, m), 7.10-6.95 (3H, m), 4.42 (2H, t, J= 7.3 Hz), 2.96 (4H, t, J = 4.6 Hz), 2.82 (2H, t, J = 7.6 Hz), 2.75-2.50(4H, m), 2.40 (3H, s), 2.33 (3H, s) 116a (CDCl3) δ: 8.83 (1H, s),7.87-7.77 (2H, m), 7.52 (1H, s), 501 7.34 (1H, dd, J = 8.5, 2.7 Hz),7.00 (1H, d, J = 8.8 Hz), 5.68 (1H, ddt, J = 16.8, 10.2, 6.3 Hz), 5.01(1H, dd, J = 10.2, 1.5 Hz), 4.89 (1H, dd, J = 16.8, 1.2 Hz), 4.81 (2H,d, J = 6.3 Hz), 3.86 (4H, t, J = 4.4 Hz), 3.65 (2H, s), 2.90 (4H, t, J =4.4 Hz), 2.35 (6H, s), 2.34 (3H, s). 117a (CDCl3) δ: 8.82 (1H, s), 7.81(1H, t, J = 7.8 Hz), 7.73 (1H, d, J = 7.8 Hz), 460 7.46 (2H, d, J = 8.8Hz), 7.38 (1H, d, J = 7.8 Hz), 6.88 (2H, d, J = 8.8 Hz), 5.68 (1H, ddt,J = 17.1, 10.2, 6.3 Hz), 5.00 (1H, dd, J = 10.2, 1.0 Hz), 4.89 (1H, dd,J = 17.1, 1.0 Hz), 4.80 (2H, dd, J = 6.3, 0.5 Hz), 4.53 (1H, septet, J =5.9 Hz), 3.63 (2H, s), 2.34 (6H, s), 1.35 (6H, d, J = 5.9 Hz). 118a(CDCl3) δ: 8.85 (1H, s), 7.89 (1H, t, J = 7.8 Hz), 7.75 (1H, d, J = 7.8Hz), 588 7.71-7.66 (1H, m), 7.42 (2H, d, J = 7.3 Hz), 7.11 (1H, d, J =8.3 Hz), 5.74-5.62 (1H, m), 5.01 (1H, d, J = 10.2 Hz), 4.89 (1H, d, J =17.1 Hz), 4.85-4.71 (2H, m), 4.80 (2H, s), 4.16 (2H, s), 3.87-3.74 (2H,m), 3.74-3.65 (2H, m), 3.63 (2H, s), 3.46 (3H, s), 2.99-2.93 (4H, m),2.34 (6H, s). 119a (CDCl3) δ: 8.91 (1H, s), 7.99-7.90 (3H, m), 7.77-7.70(3H, 444 m), 7.49 (1H, d, J = 7.8 Hz), 5.80-5.60 (1H, m), 5.03 (1H, dd,J = 10.0, 1.2 Hz), 4.91 (1H, dd, J = 17.1, 1.5 Hz), 4.80 (2H, d, J = 5.9Hz), 3.69 (2H, s), 3.49 (2H, s), 2.62 (3H, s), 2.38 (3H, s). 120a(CDCl3) δ: 8.84 (1H, s), 7.87 (1H, t, J = 7.8 Hz), 7.75 (1H, d, J = 7.8Hz), 558 7.61-7.55 (1H, m), 7.39 (1H, d, J = 7.3 Hz), 7.37-7.34 (1H, m),7.21 (1H, d, J = 8.8 Hz), 5.71-5.63 (1H, m), 5.00 (1H, dd, J = 10.2, 1.0Hz), 4.88 (1H, dd, J = 17.1, 1.5 Hz), 4.84-4.77 (4H, m), 3.61 (2H, s),3.02 (4H, t, J = 4.6 Hz), 2.83-2.64 (4H, m), 2.33 (3H, s), 1.11 (3H, d,J = 6.3 Hz). 121a (CDCl3) δ: 8.82 (1H, s), 7.47-7.23 (6H, m), 6.96 (1H,d, J = 8.3 Hz), 555 5.75-5.64 (1H, m), 5.09 (1H, d, J = 10.2 Hz), 4.96(1H, d, J = 16.6 Hz), 4.39 (2H, d, J = 6.3 Hz), 3.62 (2H, s), 3.05-2.96(1H, m), 2.91 (4H, t, J = 4.6 Hz), 2.67-2.43 (6H, m), 2.38 (3H, s), 2.26(3H, s), 1.03 (6H, d, J = 6.3 Hz), 0.99 (3H, t, J = 7.3 Hz). 122a(CDCl3) δ: 8.90-8.70 (1H, m), 7.47 (1H, t, J = 7.8 Hz), 555 7.43-7.29(5H, m), 6.96 (1H, d, J = 8.3 Hz), 5.75-5.64 (1H, m), 5.09 (1H, dd, J =10.2, 1.0 Hz), 4.96 (1H, dd, J = 17.1, 1.5 Hz), 4.38 (2H, d, J = 6.3Hz), 3.70 (4H, t, J = 4.6 Hz), 3.56 (2H, s), 2.92 (4H, t, J = 4.9 Hz),2.71-2.52 (4H, m), 2.51-2.43 (4H, m), 2.38 (3H, s), 2.26 (3H, s). 123a(CDCl3) δ: 8.81 (1H, s), 7.27-7.46 (6H, m), 6.94 (1H, d, J = 8.5 Hz),541 5.62-5.75 (1H, m), 5.07 (1H, d, J = 10.3 Hz), 4.95 (1H, d, J = 17.1Hz), 4.37 (2H, d, J = 5.9 Hz), 3.62 (2H, s), 2.90 (4H, t, J = 4.5 Hz),2.50-2.63 (4H, m), 2.54 (4H, q, J = 7.1 Hz), 2.36 (3H, s), 2.25 (3H, s),1.04 (6H, t, J = 7.1 Hz). 124a (CDCl3) δ: 8.82 (1H, s), 7.82 (1H, t, J =7.8 Hz), 7.74 (1H, d, J = 7.8 Hz), 514 7.47 (2H, d, J = 8.8 Hz), 7.38(1H, d, J = 7.3 Hz), 6.92 (1H, d, J = 9.3 Hz), 5.73-5.63 (1H, m), 5.00(1H, dd, J = 10.0, 1.2 Hz), 4.89 (1H, dd, J = 17.1, 1.5 Hz), 4.80 (2H,d, J = 6.3 Hz), 3.63 (2H, s), 3.23 (4H, t, J = 4.9 Hz), 2.72-2.63 (4H,m), 2.52 (2H, t, J = 7.1 Hz), 2.33 (6H, s), 1.16 (3H, t, J = 7.3 Hz).125a (CDCl3) δ: 8.87-8.76 (1H, m), 7.82 (1H, t, J = 7.8 Hz), 7.74 (1H,528 d, J = 7.8 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.38 (1H, d, J = 7.3 Hz),6.92 (2H, d, J = 8.8 Hz), 5.74-5.62 (1H, m), 5.00 (1H, d, J = 10.2 Hz),4.89 (1H, dd, J = 17.1, 1.5 Hz), 4.80 (2H, d, J = 6.3 Hz), 3.63 (2H, s),3.32-3.20 (4H, m), 2.90-2.70 (4H, m), 2.34 (6H, s), 1.16 (6H, d, J = 5.9Hz). 126a (CDCl3) δ: 8.81 (1H, s), 7.81-7.63 (1H, m), 7.48-7.28 (5H, 557m), 6.96 (1H, d, J = 8.3 Hz), 5.75-5.64 (1H, m), 5.09 (1H, dd, J = 10.7,1.0 Hz), 4.97 (1H, dd, J = 17.1, 1.0 Hz), 4.40 (2H, d, J = 6.3 Hz), 3.63(2H, s), 3.52 (2H, t, J = 5.9 Hz), 3.33 (3H, s), 2.91 (4H, t, J = 4.6Hz), 2.67-2.49 (4H, m), 2.63 (2H, t, J = 5.9 Hz), 2.37 (3H, s), 2.29(3H, s), 2.26 (3H, s). 127a (CDCl3) δ: 8.86 (1H, s), 8.54 (1H, d, J =4.9 Hz), 7.90-7.85 (2H, 375 m), 7.61 (2H, d, J = 8.4 Hz), 7.60 (1H,brs), 7.35 (2H, d, J = 8.4 Hz), 7.19-7.16 (1H, m), 5.67 (1H, ddt, J =17.2, 10.0, 6.4 Hz), 5.03 (1H, d, J = 10.0 Hz), 4.93 (1H, d, J = 17.2Hz), 4.79 (2H, d, J = 6.4 Hz). E 128a (CDCl3) δ: 8.86 (1H, s), 8.53 (1H,td, J = 1.5, 4.9 Hz), 7.88 (2H, 430 d, J = 2.9 Hz), 7.71 (1H, brs), 7.55(2H, d, J = 8.3 Hz), 7.31 (2H, d, J = 8.3 Hz), 7.25 (1H, t, J = 4.4 Hz),5.69 (1H, ddt, J = 17.1, 10.0, 6.3 Hz), 5.02 (1H, dd, J = 10.0, 1.2 Hz),4.92 (1H, dd, J = 17.1, 1.0 Hz), 4.79 (2H, d, J = 6.3 Hz), 3.56 (2H, s),2.54 (4H, q, J = 7.2 Hz), 1.06 (7H, t, J = 7.1 Hz). 129a (CDCl3) δ: 8.83(1H, s), 7.74 (1H, t, J = 8.0 Hz), 7.52 (1H, s), 593 7.41 (2H, d, J =7.8 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.30 (1H, d, J = 8.8 Hz), 7.00 (1H,d, J = 8.8 Hz), 6.90 (2H, dd, J = 6.6, 2.2 Hz), 6.74 (1H, d, J = 7.8Hz), 5.65 (1H, ddt, J = 17.1, 10.2, 5.9 Hz), 5.30 (2H, s), 5.01 (1H, dd,J = 10.2, 1.5 Hz), 4.89 (1H, dd, J = 17.1, 1.5 Hz), 4.66 (2H, d, J = 5.9Hz), 3.80 (3H, s), 2.93 (4H, t, J = 4.9 Hz), 2.59 (4H, s), 2.38 (3H, s),2.31 (3H, s). 130a (DMSO-d6) δ: 8.83 (1H, s), 7.85 (1H, t, J = 7.8 Hz),7.70 (1H, br 473 s), 7.41 (1H, dd, J = 9.0, 2.2 Hz), 7.27 (1H, d, J =6.8 Hz), 6.98 (1H, d, J = 8.8 Hz), 6.62 (1H, d, J = 7.8 Hz), 5.67 (1H,ddt, J = 17.1, 10.2, 5.9 Hz), 5.03 (1H, dd, J = 10.2, 1.0 Hz), 4.90 (1H,dd, J = 17.1, 1.0 Hz), 4.56 (2H, s), 3.32 (4H, s), 2.89 (4H, brs), 2.49(3H, s), 2.22 (3H, s). 131a (CDCl3) δ: 8.83 (1H, s), 8.03-7.79 (3H, m),7.51 (1H, s), 588 7.33 (1H, d, J = 8.4 Hz), 7.18-6.98 (2H, m), 5.71-5.66(1H, m), 5.01 (1H, d, J = 10.0 Hz), 4.91 (1H, d, J = 17.6 Hz), 4.80 (1H,d, J = 6.3 Hz), 4.61, 4.57 (2H, s), 3.76, 3.72 (3H, s), 3.04-2.95 (7H,m), 2.66 (4H, brs), 2.41 (3H, s), 2.32 (3H, s). 132a (CDCl3) δ: 8.83(1H, s), 7.86 (1H, d, J = 7.8 Hz), 7.80 (1H, t, J = 7.8 Hz), 557 7.52(1H, s), 7.45 (1H, s), 7.31 (1H, d, J = 8.3 Hz), 7.20 (1H, dd, J = 7.3,1.0 Hz), 7.02 (1H, d, J = 8.3 Hz), 5.69-5.59 (1H, m), 4.98 (1H, d, J =11.2 Hz), 4.90-4.84 (3H, m), 3.70 (3H, s), 2.95 (4H, t, J = 4.6 Hz),2.61 (3H, s), 2.38 (4H, s), 2.33 (3H, s), 1.63 (6H, s). 133a (CDCl3) δ:8.84 (1H, s), 8.55 (1H, td, J = 3.2, 1.6 Hz), 7.89 (2H, dd, 389 J = 4.9,1.5 Hz), 7.52 (2H, s), 7.38-7.27 (3H, m), 5.69 (1H, ddt, J = 17.1, 10.1,6.3 Hz), 5.02 (1H, dd, J = 10.2, 1.0 Hz), 4.92 (1H, dd, J = 17.1, 1.0Hz), 4.79 (2H, d, J = 6.3 Hz), 4.69 (2H, s), 2.39 (3H, s), 1.27 (OH, d,J = 6.8 Hz), 0.00 (5H, t, J = 3.2 Hz). 134a (CDCl3) δ: 8.85 (1H, s),8.54-8.52 (1H, m), 7.94-7.85 (2H, 444 m), 7.49 (2H, s), 7.29 (2H, s),7.26-7.23 (1H, m), 5.69 (1H, ddt, J = 17.1, 10.2, 6.3 Hz), 5.02 (4H, d,J = 10.2 Hz), 4.92 (4H, d, J = 17.1 Hz), 4.79 (4H, d, J = 6.3 Hz), 3.50(2H, s), 2.52 (4H, q, J = 7.0 Hz), 2.38 (3H, s), 1.04 (7H, t, J = 7.1Hz). 135a (CDCl3) δ: 8.84 (1H, s), 7.82 (1H, t, J = 7.8 Hz), 7.76 (1H,d, J = 8.3 Hz), 514 7.50 (1H, s), 7.40 (2H, dd, J = 7.3, 1.0 Hz), 7.33(1H, dd, J = 8.8, 2.9 Hz), 7.02 (1H, d, J = 8.8 Hz), 5.68 (1H, ddt, J =17.1, 10.0, 6.3 Hz), 5.01 (1H, dd, J = 10.0, 1.2 Hz), 4.90 (1H, dd, J =17.1, 1.5 Hz), 4.83 (2H, d, J = 6.3 Hz), 2.98 (4H, t, J = 4.4 Hz), 2.67(4H, brs), 2.43 (3H, s), 2.32 (3H, s), 1.54 (6H, s). 136a (CDCl3) δ:8.81 (1H, s), 7.59-7.31 (6H, m), 6.83 (2H, d, J = 8.8 Hz), 513 5.75-5.63(1H, m), 5.11 (1H, d, J = 1.0 Hz), 5.09 (2H, dd, J = 10.2, 1.0 Hz), 4.97(1H, dd, J = 17.1, 1.0 Hz), 4.39 (2H, d, J = 5.9 Hz), 3.83 (2H, s),3.50-3.38 (6H, m), 3.04 (3H, s), 2.45-2.21 (6H, m). 137a (CDCl3) δ: 8.82(1H, s), 7.84 (1H, t, J = 7.8 Hz), 7.74 (1H, d, J = 7.8 Hz), 514 7.52(2H, d, J = 8.8 Hz), 7.42 (1H, d, J = 7.3 Hz), 6.88 (2H, d, J = 9.3 Hz),5.74-5.63 (1H, m), 5.01 (1H, d, J = 10.2 Hz), 4.89 (1H, d, J = 17.1 Hz),4.80 (2H, d, J = 6.3 Hz), 3.87 (2H, s), 3.66 (2H, s), 3.52-3.45 (4H, m),3.05 (3H, s), 2.36 (6H, s). 138a (CDCl3) δ: 8.81 (1H, s), 7.49-7.40 (6H,m), 7.34 (2H, d, J = 7.8 Hz), 527 6.82 (2H, d, J = 8.8 Hz), 5.75-5.63(1H, m), 5.09 (1H, dd, J = 10.2, 1.0 Hz), 4.97 (1H, dd, J = 17.1, 1.0Hz), 4.38 (2H, d, J = 5.9 Hz), 3.59-3.51 (4H, m), 3.44-3.38 (4H, m),3.04 (3H, s), 2.82-2.78 (2H, m), 2.30 (6H, s). 139a (CDCl3) δ: 8.82 (1H,s), 7.83 (1H, t, J = 7.8 Hz), 7.74 (1H, d, J = 8.3 Hz), 528 7.48 (2H, d,J = 8.8 Hz), 7.40 (1H, d, J = 7.3 Hz), 6.87 (2H, d, J = 8.8 Hz),5.74-5.62 (1H, m), 5.01 (1H, d, J = 10.2 Hz), 4.89 (1H, d, J = 17.1 Hz),4.79 (2H, d, J = 6.3 Hz), 3.64 (2H, s), 3.59-3.55 (2H, m), 3.47-3.42(4H, m), 3.05 (3H, s), 2.85-2.81 (2H, m), 2.35 (6H, s). 140a (CDCl3) δ:8.85 (1.0H, s), 7.82 (1.0H, t, J = 7.8 Hz), 7.74 (1.0H, 474 d, J = 7.8Hz), 7.59 (1.0H, brs), 7.52 (2.0H, d, J = 8.8 Hz), 7.37 (2.0H, d, J =8.3 Hz), 7.34 (1.0H, d, J = 7.3 Hz), 5.70 (1.0H, ddt, J = 16.8, 10.5,5.9 Hz), 5.04 (1.0H, dd, J = 10.5, 0.7 Hz), 4.93 (1.0H, dd, J = 16.8,1.2 Hz), 4.75 (2.0H, d, J = 5.9 Hz), 3.92 (1.0H, s), 3.57 (2.0H, s),2.99-2.93 (1.0H, m), 1.13 (3.0H, d, J = 6.3 Hz), 1.10 (3.0H, d, J = 6.8Hz). 141a (CDCl3) δ: 8.84 (1H, s), 7.93 (1H, t, J = 7.8 Hz), 7.80 (1H,d, J = 7.8 Hz), 527 7.51 (1H, d, J = 7.8 Hz), 7.46 (1H, brs), 7.37 (1H,brs), 7.04 (1H, d, J = 8.8 Hz), 5.70 (1H, tdd, J = 6.3, 16.6, 10.0 Hz),5.05 (1H, dd, J = 10.0, 1.7 Hz), 4.94 (1H, dd, J = 16.6, 1.5 Hz), 4.74(2H, d, J = 6.3 Hz), 4.14 (1H, brs), 3.01 (4H, brs), 2.57-2.43 (4H, m),2.32 (3H, s), 2.14-2.06 (1H, m), 1.97-1.85 (1H, m). 142a (CDCl3) δ: 8.84(1H, s), 7.80 (1H, t, J = 7.8 Hz), 7.64 (1H, brs), 529 7.42 (1H, brs),7.35 (1H, dd, J = 8.8, 2.4 Hz), 7.09 (1H, d, J = 7.8 Hz), 7.03 (1H, d, J= 8.3 Hz), 5.77-5.64 (1H, m), 5.11-4.95 (2H, m), 4.65 (2H, brs), 2.98(6H, brs), 2.67 (4H, brs), 2.43 (3H, brs), 2.32 (3H, s), 1.24 (6H, s).143a (CDCl3) δ: 8.83 (1H, s), 7.87 (1H, t, J = 8.0 Hz), 7.74 (1H, d, J =7.3 Hz), 515 7.51 (2H, d, J = 8.8 Hz), 7.36 (1H, d, J = 7.3 Hz), 6.88(2H, d, J = 9.3 Hz), 5.76-5.65 (1H, m), 5.05 (1H, d, J = 10.2 Hz), 4.93(1H, d, J = 17.1 Hz), 4.74 (2H, d, J = 6.3 Hz), 4.06-3.95 (1H, m), 3.87(2H, s), 3.52-3.45 (4H, m), 3.06 (3H, s), 1.59 (6H, s). 144a (CDCl3) δ:8.87 (1H, s), 7.89 (1H, t, J = 7.8 Hz), 7.75 (1H, d, J = 7.3 Hz), 5437.58 (2H, d, J = 8.8 Hz), 7.38 (1H, d, J = 6.8 Hz), 7.30 (2H, d, J = 8.8Hz), 5.76-5.66 (1H, m), 5.05 (1H, dd, J = 10.2, 1.0 Hz), 4.94 (1H, dd, J= 17.1, 1.0 Hz), 4.75 (2H, d, J = 6.3 Hz), 3.95 (1H, brs), 3.63 (2H, t,J = 4.9 Hz), 3.52 (2H, s), 3.47 (2H, t, J = 4.9 Hz), 2.48-2.40 (4H, m),2.09 (3H, s), 1.59 (6H, s). 145a (CDCl3) δ: 8.87 (1H, s), 7.90 (1H, t, J= 7.8 Hz), 7.75 (1H, d, J = 7.3 Hz), 579 7.58 (2H, d, J = 8.3 Hz), 7.38(1H, d, J = 7.8 Hz), 7.29 (2H, d, J = 8.3 Hz), 5.76-5.66 (1H, m), 5.05(1H, dd, J = 10.2, 1.0 Hz), 4.94 (1H, dd, J = 17.1, 1.0 Hz), 4.75 (2H,d, J = 5.9 Hz), 3.93 (1H, s), 3.54 (2H, s), 3.29-3.22 (4H, m), 2.79 (3H,s), 2.60-2.54 (4H, m), 1.59 (6H, s). 146a (CDCl3) δ: 8.86 (s, 1H), 7.90(t, 1H, J = 7.8 Hz), 7.78 (d, 1H, J = 7.8 Hz), 488 7.55 (d, 2H, J = 8.3Hz), 7.36 (d, 1H, J = 7.8 Hz), 7.32 (d, 2H, J = 8.3 Hz), 5.71 (ddt, 1H,J = 17.1, 10.2, 5.9 Hz), 5.05 (d, 1H, J = 10.2 Hz), 4.94 (d, 1H, J =17.1 Hz), 4.75 (d, 2H, J = 5.9 Hz), 3.94 (brs, 1H), 3.51 (s, 2H), 2.91(t, 1H, J = 6.3 Hz), 2.17 (s, 3H), 1.59 (s, 6H), 1.08 (d, 6H, J = 6.3Hz). 147a (CDCl3) δ: 8.87 (s, 1H), 7.90 (t, 1H, J = 7.8 Hz), 7.77 (d,1H, J = 7.8 Hz), 488 7.56 (d, 2H, J = 8.3 Hz), 7.36 (d, 1H, J = 7.8 Hz),7.30 (d, 2H, J = 8.3 Hz), 5.71 (ddt, 1H, J = 17.1, 10.2, 6.3 Hz), 5.05(d, 1H, J = 10.2 Hz), 4.94 (d, 1H, J = 17.1 Hz), 4.75 (d, 2H, J = 6.3Hz), 3.93 (brs, 1H), 3.48 (s, 2H), 2.34 (t, 2H, J = 7.3 Hz), 2.21 (s,3H), 1.59 (s, 6H), 1.49-1.59 (m, 2H), 0.91 (t, 3H, J = 7.3 Hz). 148a(CDCl3) δ: 8.87 (s, 1H), 7.90 (t, 1H, J = 7.8 Hz), 7.76 (d, 1H, J = 7.8Hz), 502 7.57 (d, 2H, J = 8.3 Hz), 7.37 (d, 1H, J = 7.8 Hz), 7.32 (d,2H, J = 8.3 Hz), 5.71 (ddt, 1H, J = 17.1, 10.2, 6.3 Hz), 5.05 (d, 1H, J= 10.2 Hz), 4.94 (d, 1H, J = 17.1 Hz), 4.75 (d, 2H, J = 6.3 Hz), 3.92(brs, 1H), 3.66-3.79 (brm, 4H), 3.50 (s, 2H), 2.38-2.54 (brm, 4H), 1.59(s, 6H). 149a (CDCl3) δ: 8.86 (s, 1H), 7.90 (t, 1H, J = 7.8 Hz), 7.77(d, 1H, J = 7.8 Hz), 486 7.56 (d, 2H, J = 8.8 Hz), 7.36 (d, 3H, J = 7.8Hz), 7.32 (d, 3H, J = 8.8 Hz), 5.71 (ddt, 1H, J = 17.1, 10.2, 5.9 Hz),5.05 (d, 1H, J = 10.2 Hz), 4.94 (d, 1H, J = 17.1 Hz), 4.76 (d, 2H, J =5.9 Hz), 3.95 (brs, 1H), 3.61 (s, 2H), 2.48-2.56 (brm, 4H), 1.76-1.84(brm, 5H), 1.59 (s, 6H). 150a (CDCl3) δ: 8.82 (1H, s), 7.78 (1H, t, J =7.8 Hz), 7.44 (2H, d, J = 8.3 Hz), 541 7.07 (1H, d, J = 7.8 Hz), 6.92(2H, d, J = 9.3 Hz), 5.77-5.64 (1H, brm), 5.12-4.95 (2H, brm), 4.63 (2H,brs), 3.16 (4H, s), 2.98 (2H, s), 2.80 (4H, s), 1.69 (1H, brs), 1.24(6H, s), 0.50 (4H, brs). 151a (CDCl3) δ: 8.84 (1H, s), 7.87 (1H, dd, J =8.3, 7.8 Hz), 7.74 (1H, 593 d, J = 7.3 Hz), 7.48 (2H, d, J = 8.8 Hz),7.35 (1H, d, J = 8.3 Hz), 6.92 (2H, d, J = 8.8 Hz), 5.70 (1H, ddt, J =17.1, 10.2, 5.9 Hz), 5.05 (1H, dd, J = 10.2, 1.5 Hz), 4.94 (1H, dd, J =17.1, 1.0 Hz), 4.74 (2H, d, J = 5.9 Hz), 3.33-3.14 (5H, m), 3.07 (3H,s), 3.04-2.93 (2H, m), 2.86-2.62 (5H, m), 1.59 (6H, s). 152a (CDCl3) δ:8.86 (1.0H, s), 7.89 (1.0H, t, J = 7.8 Hz), 7.73 (1.0H, 515 d, J = 8.8Hz), 7.63 (2.0H, d, J = 8.8 Hz), 7.37 (1.0H, d, J = 8.3 Hz), 7.26 (2.0H,d, J = 9.8 Hz), 5.76-5.65 (1.0H, m), 5.05 (1.0H, dd, J = 10.0, 1.2 Hz),4.93 (1.0H, dd, J = 17.1, 1.2 Hz), 4.75 (2.0H, d, J = 6.3 Hz), 4.06-3.95(1.0H, m), 3.72 (2.0H, t, J = 5.4 Hz), 3.31 (2.0H, s), 2.81 (2.0H, t, J= 5.4 Hz), 2.43 (3.0H, s), 1.59 (6.0H, s). 153a (CDCl3) δ: 8.83 (1H, s),7.83 (1H, dd, J = 8.0, 7.6 Hz), 7.74 (1H, 586 d, J = 8.0 Hz), 7.47 (2H,d, J = 8.8 Hz), 7.33 (1H, d, J = 7.6 Hz), 6.92 (2H, d, J = 8.8 Hz), 5.69(1H, ddt, J = 16.8, 10.4, 5.6 Hz), 5.04 (1H, d, J = 10.4 Hz), 4.92 (1H,d, J = 16.8 Hz), 4.74 (2H, d, J = 5.6 Hz), 3.22 (4H, t, J = 4.8 Hz),3.04 (3H, s), 2.96 (3H, s), 2.86 (2H, t, J = 7.6 Hz), 2.74 (2H, t, J =4.8 Hz), 2.62 (2H, t, J = 7.6 Hz), 1.59 (6H, s). 154a (CDCl3) δ: 8.83(1H, s), 8.30 (1H, br), 7.86 (1H, dd, J = 8.0, 7.6 Hz), 573 7.78 (1H,dd, J = 8.0, 2.8 Hz), 7.68 (1H, d, J = 8.8 Hz), 6.66 (1H, d, J = 8.8Hz), 5.69 (1H, ddt, J = 16.8, 10.4, 5.6 Hz), 5.04 (1H, d, J = 10.4 Hz),4.92 (1H, d, J = 16.8 Hz), 4.73 (2H, d, J = 5.6 Hz), 3.58 (4H, t, J =4.8 Hz), 3.26 (2H, s), 3.11 (3H, s), 2.98 (3H, s), 2.70 (4H, t, J = 4.8Hz), 2.62 (2H, t, J = 7.6 Hz), 1.58 (6H, s). 155a (CDCl3) δ: 8.83 (1H,s), 7.86 (1H, dd, J = 8.0, 7.6 Hz), 7.74 (1H, 585 d, J = 8.0 Hz), 7.47(2H, d, J = 8.8 Hz), 7.31 (1H, d, J = 7.6 Hz), 6.92 (2H, d, J = 8.8 Hz),5.69 (1H, ddt, J = 16.8, 10.4, 5.6 Hz), 5.04 (1H, d, J = 10.4 Hz), 4.92(1H, d, J = 16.8 Hz), 4.74 (2H, d, J = 5.6 Hz), 3.99 (1H, brs),3.40-3.45 (1H, m), 3.14-3.24 (4H, m), 2.92 (2H, br), 2.61 (2H, br), 2.30(1H, br), 2.18 (1H, br), 1.68-1.88 (4H, m), 1.59 (6H, s). 156a (CDCl3)δ: 8.83 (1H, s), 7.89-7.75 (2H, m), 7.49 (1H, s), 500 7.42 (1H, s), 7.32(1H, dd, J = 8.8, 2.4 Hz), 7.24 (1H, d, J = 6.3 Hz), 7.02 (1H, dd, J =8.5, 3.2 Hz), 5.69 (1H, ddt, J = 17.1, 10.2, 6.3 Hz), 5.02 (1H, dd, J =10.2, 1.5 Hz), 4.92 (1H, dd, J = 17.1, 1.5 Hz), 4.77 (2H, d, J = 6.3Hz), 3.90 (1H, s), 2.96 (4H, t, J = 4.6 Hz), 2.63 (3H, s), 2.51 (2H, s),2.40 (3H, s), 2.32 (3H, s). 157a (CDCl3) δ: 8.84 (s, 1H), 7.85 (dd, 1H,J = 7.8, 8.0 Hz), 7.74 (d, 1H, 556 J = 8.0 Hz), 7.46 (d, 2H, J = 8.8Hz), 7.34 (d, 1H, J = 7.8 Hz), 6.90 (d, 2H, J = 8.8 Hz), 5.70 (ddt, 1H,J = 17.1, 10.2, 6.3 Hz), 5.04 (dd, 1H, J = 10.2, 1.0 Hz), 4.94 (dd, 1H,J = 17.1, 1.0 Hz), 4.74 (d, 2H, J = 6.3 Hz), 4.36-4.26 (brm, 1H), 3.96(s, 1H), 2.79-2.72 (m, 1H), 2.70-2.58 (brm, 2H), 2.25-2.11 (brm, 2H),2.10-1.63 (m, 10H), 1.58 (s, 6H). 158a (CDCl3) δ: 8.84 (1H, s), 7.86(1H, t, J = 7.8 Hz), 7.73 (1H, d, J = 7.8 Hz), 516 7.48 (2H, d, J = 8.8Hz), 7.35 (1H, d, J = 7.8 Hz), 6.91 (2H, d, J = 8.8 Hz), 5.70 (1H, ddt,J = 17.1, 10.2, 6.3 Hz), 5.04 (1H, d, J = 10.2 Hz), 4.94 (1H, dd, J =17.1, 1.0 Hz), 4.74 (2H, d, J = 6.3 Hz), 4.39-4.27 (1H, brm), 4.01-3.88(1H, brm), 2.84-2.69 (2H, brm), 2.49-2.29 (2H, brm), 2.37 (3H, s),2.15-2.02 (2H, brm), 1.97-1.83 (2H, brm), 1.59 (6H, s). 159a (CD3OD) δ:8.82 (1H, s), 7.89 (1H, dd, J = 8.0, 7.6 Hz), 7.75 (1H, 540 d, J = 8.0Hz), 7.49 (2H, d, J = 8.8 Hz), 7.47 (1H, d, J = 7.6 Hz), 6.94 (2H, d, J= 8.8 Hz), 5.69 (1H, ddt, J = 16.8, 10.4, 5.6 Hz), 5.04 (1H, d, J = 10.4Hz), 4.92 (1H, d, J = 16.8 Hz), 4.77 (2H, d, J = 5.6 Hz), 3.21 (4H, t, J= 4.8 Hz), 2.79 (2H, t, J = 6.8 Hz), 2.72 (4H, t, J = 4.8 Hz), 2.62 (2H,t, J = 6.8 Hz), 1.59 (6H, s). 160a (CDCl3) δ: 8.82 (1H, s), 7.81 (1H, t,J = 7.8 Hz), 7.72 (1H, d, J = 7.8 Hz), 486 7.46 (2H, d, J = 8.8 Hz),7.25 (1H, d, J = 7.3 Hz), 6.92 (2H, d, J = 9.3 Hz), 5.69 (1H, ddt, J =17.1, 10.2, 6.3 Hz), 5.02 (1H, dd, J = 10.2, 1.5 Hz), 4.92 (1H, dd, J =17.1, 1.5 Hz), 4.75 (2H, d, J = 6.3 Hz), 3.91 (2H, s), 3.21 (4H, t, J =4.9 Hz), 2.62 (4H, t, J = 4.9 Hz), 2.51 (3H, s), 2.38 (3H, s). 161a(CDCl3) δ: 8.80 (1H, s), 7.57 (1H, s), 7.47-7.46 (2H), 7.42 (2H, 526 d,J = 8.8 Hz), 7.29 (1H, m), 6.87 (2H, d, J = 8.8 Hz), 5.70 (1H, ddd, J =17.2, 10.0, 6.4 Hz), 5.10 (1H, d, J = 10.0 Hz), 4.98 (1H, d, J = 17.2Hz), 4.37 (1H, d, J = 6.4 Hz), 3.11 (4H, m), 2.79 (4H, m), 1.87-1.68(1H, m), 1.61 (6H, s), 0.50-0.49 (4H, m). 162a (CDCl3) δ: 8.86 (1H, s),7.87 (1H, t, J = 8.0 Hz), 7.75 (1H, dd, J = 8.0, 501 1.0 Hz), 7.58 (1H,brs), 7.37 (1H, dd, J = 8.0, 1.0 Hz), 7.23 (1H, t, J = 8.0 Hz), 7.11(1H, d, J = 8.0 Hz), 7.11-7.07 (1H, m), 6.71 (1H, dd, J = 8.0, 1.7 Hz),5.70 (1H, ddt, J = 17.3, 10.0, 5.9 Hz), 5.04 (1H, dd, J = 10.0, 1.5 Hz),4.93 (1H, dd, J = 17.3, 1.5 Hz), 4.74 (2H, d, J = 5.9 Hz), 3.97 (1H,brs), 3.23-3.11 (4H, m), 2.62-2.51 (4H, m), 2.37 (3H, s), 1.58 (6H, s).163a (CDCl3) δ: 8.87 (1H, s), 7.90 (1H, t, J = 7.8 Hz), 7.77 (1H, d, J =7.8 Hz), 529 7.60-7.47 (1H, brm), 7.55 (2H, d, J = 8.3 Hz), 7.37 (1H, d,J = 7.8 Hz), 7.33 (2H, d, J = 8.3 Hz), 5.71 (1H, ddt, J = 17.1, 10.2,6.3 Hz), 5.05 (1H, dd, J = 10.2, 1.0 Hz), 4.94 (1H, dd, J = 17.1, 1.0Hz), 4.75 (2H, d, J = 6.3 Hz), 3.94 (1H, brs), 3.63 (2H, s), 2.78-2.69(6H, m), 2.68-2.61 (2H, m), 2.40 (3H, s), 1.90-1.80 (2H, m), 1.59 (6H,s). 164a (CDCl3) δ: 8.87 (1H, s), 7.90 (1H, t, J = 8.0 Hz), 7.76 (1H, d,J = 8.0 Hz), 515 7.60-7.50 (1H, brm), 7.56 (2H, d, J = 8.4 Hz), 7.37(1H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.4 Hz), 5.71 (1H, ddt, J = 17.2,10.4, 6.3 Hz), 5.05 (1H, d, J = 10.4 Hz), 4.94 (1H, d, J = 17.2 Hz),4.75 (2H, d, J = 6.3 Hz), 3.51 (2H, s), 2.61-2.40 (4H, brm), 2.33 (3H,s), 1.82-1.62 (4H, brm), 1.59 (6H, s). 165a (CDCl3) δ: 8.87 (1H, s),7.90 (1H, t, J = 8.0 Hz), 7.77 (1H, d, J = 8.0 Hz), 541 7.60 (1H, brs),7.56 (3H, d, J = 8.4 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.4Hz), 5.87 (1H, ddt, J = 18.4, 11.0, 6.7 Hz), 5.71 (1H, ddt, J = 17.0,10.2, 6.3 Hz), 5.19 (1H, d, J = 18.4 Hz), 5.15 (1H, d, J = 11.0 Hz),5.05 (1H, d, J = 10.2 Hz), 4.94 (1H, d, J = 17.0 Hz), 4.75 (2H, d, J =6.3 Hz), 3.94 (1H, brs), 3.51 (2H, s), 3.02 (2H, d, J = 6.7 Hz),2.68-2.36 (8H, brm), 1.59 (6H, s). 166a (CDCl3) δ: 8.82 (1H, s),7.82-7.61 (1H, m), 7.78 (1H, t, J = 7.8 Hz), 559 7.44 (2H, d, J = 8.8Hz), 7.08 (1H, d, J = 7.8 Hz), 6.92 (2H, d, J = 8.8 Hz), 5.81-5.61 (1H,m), 5.16-4.91 (2H, m), 4.78-4.48 (2H, m), 3.57 (2H, t, J = 5.4 Hz), 3.38(3H, s), 3.26-3.18 (4H, m), 2.98 (2H, s), 2.75-2.61 (6H, m), 1.24 (6H,s). 167a (CDCl3) δ: 8.82 (1H, s), 7.82-7.62 (1H, brm), 7.78 (2H, t, J =7.8 Hz), 573 7.44 (2H, d, J = 8.8 Hz), 7.08 (1H, d, J = 7.8 Hz), 6.92(2H, d, J = 8.8 Hz), 5.79-5.62 (1H, m), 5.16-4.91 (2H, m), 4.78-4.51(2H, m), 3.62 (2H, t, J = 5.9 Hz), 3.53 (2H, q, J = 7.0 Hz), 3.24-3.17(4H, m), 2.98 (2H, s), 2.75-2.62 (4H, m), 2.67 (2H, t, J = 5.9 Hz), 1.24(6H, s), 1.22 (3H, t, J = 7.0 Hz). 168a (CD3OD) δ: 8.82 (1H, s), 7.91(1H, dd, J = 8.0, 7.6 Hz), 7.77 (1H, 571 d, J = 8.0 Hz), 7.54 (2H, d, J= 8.8 Hz), 7.54 (1H, overlapped), 6.95 (2H, d, J = 8.8 Hz), 5.68 (1H,ddt, J = 17.2, 10.4, 6.4 Hz), 5.04 (1H, d, J = 10.4 Hz), 4.92 (1H, d, J= 17.2 Hz), 4.80 (2H, d, J = 6.4 Hz), 4.16-4.19 (1H, m), 3.24 (4H, t, J= 4.8 Hz), 2.78-2.93 (4H, m), 2.57-2.61 (1H, m), 1.96-2.03 (2H, m), 1.58(6H, s), 1.50-1.75 (5H, m). 169a (CD3OD) δ: 8.82 (1H, s), 7.91 (1H, dd,J = 8.0, 7.6 Hz), 7.75 (1H, 572 d, J = 8.0 Hz), 7.56 (2H, d, J = 8.8Hz), 7.52 (1H, d, J = 7.6 Hz), 6.95 (2H, d, J = 8.8 Hz), 5.68 (1H, ddt,J = 17.2, 10.0, 5.6 Hz), 5.04 (1H, d, J = 10.0 Hz), 4.92 (1H, d, J =17.2 Hz), 4.77 (2H, d, J = 5.6 Hz), 3.78 (4H, brs), 3.20 (2H, s), 3.16(4H, t, J = 4.8 Hz), 2.33 (6H, s), 1.59 (6H, s). 170a (CD3OD) δ: 8.83(1H, s), 7.86 (1H, dd, J = 8.0, 7.6 Hz), 7.75 (1H, 584 d, J = 8.0 Hz),7.48 (2H, d, J = 8.8 Hz), 7.34 (1H, d, J = 7.6 Hz), 6.93 (2H, d, J = 8.8Hz), 5.70 (1H, ddt, J = 17.2, 10.0, 5.6 Hz), 5.04 (1H, d, J = 10.0 Hz),4.92 (1H, d, J = 17.2 Hz), 4.74 (2H, d, J = 5.6 Hz), 4.16-4.20 (1H, m),4.03-4.09 (2H, m), 3.21-3.24 (5H, brs), 2.56 (4H, t, J = 4.8 Hz), 1.89(3H, s), 1.59 (6H, s). 171a (CDCl3) δ: 8.83 (1H, s), 7.88 (1H, t, J =7.8 Hz), 7.77 (1H, d, J = 8.3 Hz), 475 7.47 (2H, d, J = 8.8 Hz), 7.36(1H, d, J = 8.3 Hz), 6.94 (2H, d, J = 8.8 Hz), 3.93 (1H, brs), 3.55 (3H,s), 3.25 (4H, t, J = 4.6 Hz), 2.67 (4H, brs), 2.42 (3H, s), 1.58 (6H,s). 172a (CDCl3) δ: 8.87 (1H, s), 7.89 (1H, dd, J = 8.0, 7.8 Hz), 7.75(1H, 606 d, J = 8.3 Hz), 7.54 (2H, d, J = 8.3 Hz), 7.51-7.41 (1H, m),7.37 (1H, d, J = 7.8 Hz), 7.20 (2H, d, J = 8.3 Hz), 5.70 (1H, ddt, J =17.1, 10.2, 6.3 Hz), 5.05 (1H, d, J = 10.2 Hz), 4.94 (1H, dd, J = 17.1,1.0 Hz), 4.74 (2H, d, J = 6.3 Hz), 3.40-2.74 (7H, m), 3.08 (3H, s),2.64-2.50 (1H, m), 2.37-2.08 (2H, m), 1.98-1.85 (3H, m), 1.59 (6H, s).173a (CDCl3) δ: 8.87 (1H, s), 7.84-7.77 (2H, m), 7.54 (2H, d, J = 8.7Hz), 606 7.20 (2H, d, J = 8.7 Hz), 7.13-7.09 (1H, m), 5.74-5.70 (1H, m),5.10-5.02 (2H, m), 4.73-4.60 (2H, m), 3.30-2.89 (6H, m) 3.09 (3H, s),3.00 (2H, s)2.61-2.10 (3H, m)1.98-1.40 (4H, m), 1.25 (6H, s). 174a(CDCl3) δ: 8.86 (1H, s), 7.83 (1H, t, J = 8.3 Hz), 7.61 (1H, brs), 6067.52 (2H, d, J = 8.8 Hz), 7.19 (2H, d, J = 8.8 Hz), 7.00 (1H, d, J = 8.3Hz), 6.64 (1H, d, J = 8.3 Hz), 5.80-5.64 (1H, m), 5.14-4.93 (2H, m),4.73-4.56 (2H, m), 3.84-3.76 (2H, m), 3.36-2.84 (6H, m), 3.07 (3H, s),2.61-2.46 (1H, m), 2.32-2.13 (2H, m), 1.94-1.82 (4H, m), 1.39 (6H, s).175a (CDCl3) δ: 8.87 (1.0H, s), 7.92 (1.0H, t, J = 8.0 Hz), 7.74 (1.0H,528 d, J = 8.0 Hz), 7.55 (2.0H, t, J = 11.3 Hz), 7.38 (1.0H, d, J = 7.4Hz), 7.28-7.24 (2.0H, m), 5.76-5.65 (1.0H, m), 5.05 (1.0H, d, J = 9.8Hz), 4.94 (1.0H, d, J = 17.0 Hz), 4.75 (2.0H, d, J = 6.3 Hz), 4.57(2.0H, s), 3.97-3.92 (1.0H, m), 3.52 (2.0H, t, J = 5.5 Hz), 3.35 (3.0H,s), 3.31 (2.0H, s), 3.27 (2.0H, t, J = 5.2 Hz), 2.72 (2.0H, t, J = 5.1Hz), 2.64 (2.0H, t, J = 5.3 Hz), 1.57 (6.0H, s). 176a (CDCl3) δ: 8.80(1H, s), 7.48-7.28 (6H, m), 7.24 (1H, d, J = 7.3 Hz), 558 6.87 (2H, d, J= 8.8 Hz), 5.69 (1H, ddt, J = 17.0, 10.2, 6.0 Hz), 5.09 (1H, dd, J =10.2, 1.0 Hz), 4.97 (1H, dd, J = 17.0, 1.0 Hz), 4.39 (2H, d, J = 5.9Hz), 3.61-3.54 (2H, m), 3.38 (3H, s), 3.24-3.16 (4H, m), 2.83 (2H, s),2.74-2.62 (7H, m), 1.25 (6H, s). 177a (CDCl3) δ: 8.83 (1H, s), 7.90 (1H,dd, J = 8.4, 7.6 Hz), 7.82 (1H, 503 d, J = 8.4 Hz), 7.48 (1H, s), 7.37(1H, d, J = 7.6 Hz), 7.34 (1H, d, J = 8.8 Hz), 7.03 (1H, d, J = 8.8 Hz),4.19 (2H, q, J = 7.2 Hz), 2.95 (4H, m), 2.61 (4H, m), 2.39 (3H, s), 2.33(3H, s), 1.58 (6H, s), 1.08 (3H, s) 178a (CD3OD) δ: 8.81 (1H, s), 7.82(2H, br), 7.37-7.47 (3H, m), 517 6.67 (2H, d, J = 8.8 Hz), 5.67 (1H,ddt, J = 16.8, 10.0, 6.4 Hz), 5.00 (1H, d, J = 10.0 Hz), 4.88 (1H, d, J= 16.8 Hz), 4.80 (2H, d, J = 6.4 Hz), 3.64 (2H, brs), 3.50 (2H, brs),2.82 (2H, brs), 2.69 (2H, br s), 2.47 (3H, s), 2.12 (2H, brs), 1.75 (3H,s), 1.69 (3H, s). 179a (CD3OD) δ: 8.82 (1H, s), 7.93 (1H, dd, J = 8.0,7.6 Hz), 7.77 (1H, 530 d, J = 8.0 Hz), 7.56 (2H, d, J = 8.8 Hz), 7.56(1H, overlapped), 6.96 (2H, d, J = 8.8 Hz), 5.68 (1H, ddt, J = 17.2,10.0, 5.6 Hz), 5.04 (1H, d, J = 10.0 Hz), 4.92 (1H, d, J = 17.2 Hz),4.81 (2H, d, J = 5.6 Hz), 3.62 (4H, t, J = 4.8 Hz), 3.17 (4H, t, J = 4.8Hz), 1.59 (6H, s). 180a (CD3OD) δ: 8.83 (1H, s), 7.81-7.90 (2H, m), 7.47(2H, d, J = 8.8 Hz), 561 7.47 (1H, overlapped), 6.92 (2H, d, J = 8.8Hz), 5.67 (1H, ddt, J = 17.2, 10.0, 5.6 Hz), 5.00 (1H, d, J = 10.0 Hz),4.88 (1H, d, J = 17.2 Hz), 4.81 (2H, d, J = 5.6 Hz), 3.20 (4H, brs),2.84 (4H, br s), 2.42 (2H, s), 1.75 (3H, s), 1.69 (3H, s), 1.21 (6H, s).181a (CDCl3) δ: 8.83 (1H, s), 7.80-7.90 (2H, m), 7.47 (2H, d, J = 8.8Hz), 503 7.47 (1H, overlapped), 6.93 (2H, d, J = 8.8 Hz), 5.67 (1H, ddt,J = 17.2, 10.0, 5.6 Hz), 5.00 (1H, d, J = 10.0 Hz), 4.88 (1H, d, J =17.2 Hz), 4.80 (2H, d, J = 5.6 Hz), 3.25 (4H, brs), 2.67 (4H, brs), 2.42(3H, s), 1.75 (3H, s), 1.69 (3H, s). 182a (CD3OD) δ: 8.82 (1H, s), 7.97(1H, dd, J = 8.0, 7.6 Hz), 7.89 (1H, 574 d, J = 8.0 Hz), 7.58 (2H, d, J= 8.8 Hz), 7.52 (2H, d, J = 7.6 Hz), 6.98 (2H, d, J = 8.8 Hz), 5.69 (1H,ddt, J = 17.2, 10.0, 5.6 Hz), 5.04 (1H, d, J = 10.0 Hz), 4.92 (1H, d, J= 17.2 Hz), 4.81 (2H, d, J = 5.6 Hz), 3.77 (4H, brs), 3.29 (2H, s), 3.18(4H, brs), 2.37 (6H, s), 1.75 (3H, s), 1.70 (3H, s). 183a (CD3OD) δ:8.82 (1H, s), 7.83 (1H, dd, J = 8.0, 7.6 Hz), 7.63 (1H, 586 brs), 7.42(2H, br), 7.26 (1H, d, J = 7.6 Hz), 6.91 (2H, d, J = 8.8 Hz), 5.70 (1H,br), 5.07 (4H, br), 3.78 (2H, s), 3.22 (4H, brs), 3.10 (3H, s), 2.97(3H, s), 2.72 (4H, s), 1.38 (6H, s). 184a (CD3OD) δ: 8.82 (1H, s),7.74-7.80 (2H, m), 7.47 (2H, d, J = 8.8 Hz), 588 7.27 (1H, br), 6.91(2H, d, J = 8.8 Hz), 5.61-5.69 (1H, m), 4.83-4.99 (4H, m), 4.60 (2H, J =47.6 Hz), 3.22 (4H, brs), 3.11 (3H, s), 2.98 (3H, s), 2.73 (4H, brs),2.72 (4H, s), 1.40 (6H, s). 185a (DMSO-d6) δ: 11.68 (1H, s), 10.18 (1H,s), 8.83 (1H, s), 500 8.06 (1H, t, J = 7.8 Hz), 7.91-7.75 (2H, m), 7.56(2H, brs), 6.90 (2H, d, J = 8.8 Hz), 5.68 (1H, ddt, J = 17.1, 10.2, 5.4Hz), 5.00 (1H, dd, J = 10.2, 1.5 Hz), 4.87 (1H, dd, J = 17.1, 1.5 Hz),4.66 (2H, d, J = 5.4 Hz), 3.08 (4H, t, J = 4.9 Hz), 2.44 (4H, t, J = 4.9Hz), 2.21 (3H, s), 2.21 (3H, s). 186a (CDCl3) δ: 8.83 (1H, s), 7.86-7.81(3H, m), 7.46 (2H, d, J = 8.8 Hz), 514 6.92 (2H, d, J = 8.8 Hz), 5.67(1H, ddt, J = 17.1, 10.2, 6.3 Hz), 5.01 (1H, dd, J = 10.2, 1.0 Hz), 4.90(1H, dd, J = 17.1, 1.0 Hz), 4.82 (2H, d, J = 6.3 Hz), 4.05 (3H, s), 3.28(4H, brs), 2.72 (4H, brs), 2.45 (3H, s), 2.30 (3H, s). 187a (CDCl3,2dropsofCD3OD) δ: 8.82 (1H, brs), 7.80 (1H, dd, J = 8.3, 536 8.0 Hz),7.56 (1H, d, J = 8.3 Hz), 7.50 (2H, d, J = 8.7 Hz), 6.93 (2H, d, J = 8.7Hz), 6.90 (1H, d, J = 8.0 Hz), 5.70-5.58 (1H, m), 5.05-4.95 (2H, m),4.87 (2H, d, J = 6.3 Hz), 3.30 (3H, s), 3.29-3.20 (4H, m), 2.87-2.57(4H, m), 2.44 (3H, s). 188a (CDCl3) δ: 8.85 (1H, s), 7.88 (1H, t, J =7.8 Hz), 7.73 (2H, d, J = 8.3 Hz), 487 7.52 (2H, d, J = 8.8 Hz), 7.36(2H, d, J = 7.3 Hz), 6.94 (2H, d, J = 9.3 Hz), 5.71 (1H, ddt, J = 17.1,10.2, 5.9 Hz), 5.05 (1H, d, J = 10.7 Hz), 4.94 (1H, d, J = 17.1 Hz),4.74 (2H, d, J = 5.9 Hz), 3.93 (1H, brs), 3.39-3.30 (6H, m), 3.21 (1H,brs), 1.59 (6H, s). 189a (DMSO-d6) δ: 10.09 (1H, s), 9.24 (1H, s), 8.81(1H, s), 7.96 (1H, 419 t, J = 8.0 Hz), 7.71 (1H, d, J = 7.3 Hz), 7.59(1H, d, J = 7.8 Hz), 7.47 (2H, d, J = 6.8 Hz), 6.72 (2H, d, J = 8.8 Hz),5.64 (1H, ddt, J = 17.1, 10.2, 5.9 Hz), 5.32 (1H, s), 4.98 (1H, dd, J =10.2, 1.0 Hz), 4.80 (1H, dd, J = 17.1, 1.5 Hz), 4.66 (2H, d, J = 5.9Hz), 1.45 (6H, s).

INDUSTRIAL APPLICABILITY

The compounds of the invention have excellent Weel kinase-inhibitoryeffect and are therefore useful in the field of medicines, especiallytreatment of various cancers.

1. A method for treating cancer, which comprises administering to asubject in need thereof a therapeutically-effective amount of a compoundof a general formula (I):

wherein; Ar¹ is an aryl group or a heteroaromatic group, which isoptionally substituted with a substituent selected from the groupconsisting of a halogen atom, a lower alkyl group, a halo-lower alkylgroup, a hydroxy-lower alkyl group, a lower alkoxy group, a loweralkanoyl group, a hydroxy-lower alkylamino group, a carbamoyl group, ahydroxy-lower alkylcarbamoyl group, a heteroaromatic group optionallysubstituted by a lower alkyl group, and a group of -Q¹-A¹-Q²-A²(R^(1a))R^(1b); A¹ is a single bond, an oxygen atom or a sulfur atom, oris an imino group optionally substituted by a lower alkyl group; A² is anitrogen atom, or is a methine or 1-vinyl-2-ylidene group optionallysubstituted by a hydroxyl group, a lower alkyl group or a hydroxy-loweralkyl group; Q¹ is a single bond, a carbonyl group, or a methylene groupoptionally substituted by a lower alkyl group; Q² is a single bond, oran ethylene group optionally substituted by a lower alkyl group; R^(1a)is a hydrogen atom, a lower alkyl group or a hydroxy-lower alkyl group,R^(1b) is a hydrogen atom, a lower alkyl group or a hydroxy-lower alkylgroup, or R^(1a) and R^(1b) together form a lower alkylene group whereinone or two or more methylene groups constituting the lower alkylenegroup may be independently replaced by an oxygen atom, a sulfur atom, asulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group ora group of —N(R^(1c))—, or substituted by a hydroxyl group or a loweralkyl group; R^(1c) is a hydrogen atom, a lower alkenyl group or a groupof -Q³-A³(R^(1d))R^(1e); A³ is a nitrogen atom, or is a methine or1-vinyl-2-ylidene group optionally substituted by a hydroxyl group, alower alkyl group or a hydroxy-lower alkyl group; Q³ is a single bond ora lower alkylene group, wherein one or two or more methylene groupsconstituting the lower alkylene group may be independently replaced byan oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group or asulfonyl group, and/or substituted by a halogen atom, a cyano group, ahydroxyl group or a lower alkyl group; R^(1d) is a hydrogen atom, ahalogen atom, a cyano group, a hydroxyl group, a lower alkyl group or ahydroxy-lower alkyl group, R^(1e) is a hydrogen atom, a halogen atom, acyano group, a hydroxyl group, a lower alkyl group or a hydroxy-loweralkyl group, or R^(1d) and R^(1e) together form a lower alkylene groupwherein one or two or more methylene groups constituting the loweralkylene group may be independently replaced by an oxygen atom, a sulfuratom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylenegroup or a group of —N(R^(1f))—, and/or substituted by a hydroxyl groupor a lower alkyl group; R^(1f) is a hydrogen atom, a lower alkyl group,a halo-lower alkyl group, a lower alkenyl group or a lower alkanoylgroup; R¹ is a lower alkenyl group, optionally substituted by a halogenatom; R² is a hydrogen atom, a lower alkyl group, a lower alkenyl groupor a lower alkynyl group, or is an aryl group, an aralkyl group or aheteroaromatic group optionally having a substituent selected from thegroup consisting of a halogen atom, a cyano group, a nitro group, acarboxyl group, a group of -Q⁴-A⁴(R^(1g))R^(1h) and a group of-Q⁵-Ar^(a), wherein one or two or more methylene groups constituting thelower alkyl group, the lower alkenyl group or the lower alkynyl groupmay be independently replaced by an oxygen atom, a sulfur atom, asulfinyl group, a sulfonyl group, a carbonyl group or a group of—N(R^(1j))—, or substituted by a halogen atom; A⁴ is a nitrogen atom, oris a methine group optionally substituted by a halogen atom, a hydroxylgroup, a lower alkyl group or a hydroxy-lower alkyl group; Ar^(a) is anaryl group or a heteroaromatic group, which may have a substituentselected from a group consisting of a halogen atom, a lower alkyl group,a halo-lower alkyl group, a hydroxy-lower alkyl group and a lower alkoxygroup; Q⁴ is a single bond or a lower alkylene group, wherein one or twoor more methylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom or a carbonyl group, orsubstituted by a lower alkyl group; Q⁵ is a single bond, an oxygen atom,a sulfur atom, a carbonyl group or a lower alkylene group, wherein oneor two or more methylene groups constituting the lower alkylene groupmay be independently replaced by an oxygen atom, a sulfur atom or acarbonyl group, or substituted by a halogen atom or a lower alkyl group;R^(1g) is a hydrogen atom, a halogen atom, a cyano group, a hydroxylgroup, a lower alkyl group, a lower alkoxy-lower alkyl group, a loweralkanoyl group, a lower alkoxycarbonyl group or a lower alkylsulfonylgroup, R^(1h) is a hydrogen atom, a halogen atom, a cyano group, ahydroxyl group, a lower alkyl group, a lower alkoxy-lower alkyl group, alower alkanoyl group, a lower alkoxycarbonyl group or a loweralkylsulfonyl group, or R^(1g) and R^(1h) together form a lower alkylenegroup, wherein one or two or more methylene groups constituting thelower alkylene group may be independently replaced by an oxygen atom, asulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group or agroup of —N(R^(1i))—, and/or substituted by a halogen atom or a loweralkyl group; R^(1i) is a hydrogen atom, a lower alkyl group or ahalo-lower alkyl group; R^(1j) is a hydrogen atom or a lower alkylgroup; R³ is a hydrogen atom or a lower alkyl group; R⁴ is a hydrogenatom, a halogen atom, a hydroxyl group, a lower alkyl group or a groupof —N(R^(1k))R^(1m); R^(1k) is a hydrogen atom or a lower alkyl group;R^(1m) is a hydrogen atom or a lower alkyl group; T is a nitrogen atomor a methine group; U is a nitrogen atom or a methine group, providedthat the compounds wherein R¹ is a methyl group and R² is anunsubstituted phenyl group are excluded, or a salt or ester thereof. 2.The method of claim 1 comprising a compound of a general formula (I-1),or a salt or ester thereof:

wherein, A¹ is a single bond, an oxygen atom or a sulfur atom, or is animino group optionally substituted by a lower alkyl group; A² is anitrogen atom, or is a methine or 1-vinyl-2-ylidene group optionallysubstituted by a hydroxyl group, a lower alkyl group or a hydroxy-loweralkyl group; Q¹ is a single bond, a carbonyl group, or a methylene groupoptionally substituted by a lower alkyl group; Q² is a single bond, oran ethylene group optionally substituted by a lower alkyl group; R^(1a)is a hydrogen atom, a lower alkyl group or a hydroxy-lower alkyl group,R^(1b) is a hydrogen atom, a lower alkyl group or a hydroxy-lower alkylgroup, or R^(1a) and R^(1b) together form a lower alkylene group whereinone or two or more methylene groups constituting the lower alkylenegroup may be independently replaced by an oxygen atom, a sulfur atom, asulfinyl group, a sulfonyl group, a carbonyl group, a vinylene group ora group of —N(R^(1c))—, and/or substituted by a hydroxyl group or alower alkyl group; R^(1c) is a hydrogen atom, a lower alkenyl group or agroup of -Q³-A³ (R^(1d))R^(1e); A³ is a nitrogen atom, or is a methineor 1-vinyl-2-ylidene group optionally substituted by a hydroxyl group, alower alkyl group or a hydroxy-lower alkyl group; Q³ is a single bond ora lower alkylene group, wherein one or two or more methylene groupsconstituting the lower alkylene group may be independently replaced byan oxygen atom, a sulfur atom, a carbonyl group, a sulfinyl group or asulfonyl group, and/or substituted by a halogen atom, a cyano group, ahydroxyl group or a lower alkyl group; R^(1d) is a hydrogen atom, ahalogen atom, a cyano group, a hydroxyl group, a lower alkyl group or ahydroxy-lower alkyl group, R^(1e) is a hydrogen atom, a halogen atom, acyano group, a hydroxyl group, a lower alkyl group or a hydroxy-loweralkyl group, or R^(1d) and R^(1e) together form a lower alkylene groupwherein one or two or more methylene groups constituting the loweralkylene group may be independently replaced by an oxygen atom, a sulfuratom, a sulfinyl group, a sulfonyl group, a carbonyl group, a vinylenegroup or a group of —N(R^(1f))—, or substituted by a hydroxyl group or alower alkyl group; R^(1f) is a hydrogen atom, a lower alkyl group, ahalo-lower alkyl group, a lower alkenyl group or a lower alkanoyl group;R⁵ is a hydrogen atom, a halogen atom, a lower alkyl group, a halo-loweralkyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a loweralkanoyl group, a hydroxy-lower alkylamino group, a carbamoyl group or ahydroxy-lower alkylcarbamoyl group; R⁶ is a hydrogen atom, a halogenatom, a lower alkyl group, a halo-lower alkyl group, a hydroxy-loweralkyl group, a lower alkoxy group, a lower alkanoyl group, ahydroxy-lower alkylamino group, a carbamoyl group or a hydroxy-loweralkylcarbamoyl group; R¹⁰ is a lower alkenyl group, which is optionallysubstituted with a halogen atom; R²⁰ is an aryl group or aheteroaromatic group, which is optionally substituted with a substituentselected from the group consisting of a halogen atom, a cyano group, anitro group, a carboxyl group, a group of -Q⁴-A⁴(R^(1g))R^(1h) and agroup of -Q⁵-Ar^(a); A⁴ is a nitrogen atom, or is a methine groupoptionally substituted by a halogen atom, a hydroxyl group, a loweralkyl group or a hydroxy-lower alkyl group; Ar^(a) is an aryl group or aheteroaromatic group, which is optionally substituted with a substituentselected from a group consisting of a halogen atom, a lower alkyl group,a halo-lower alkyl group, a hydroxy-lower alkyl group and a lower alkoxygroup; Q⁴ is a single bond or a lower alkylene group, wherein one or twoor more methylene groups constituting the lower alkylene group may beindependently replaced by an oxygen atom or a carbonyl group, orsubstituted by a lower alkyl group; Q⁵ is a single bond, an oxygen atom,a sulfur atom, a carbonyl group or a lower alkylene group, wherein oneor two or more methylene groups constituting the lower alkylene groupmay be independently replaced by an oxygen atom, a sulfur atom or acarbonyl group, or substituted by a halogen atom or a lower alkyl group;R^(1g) is a hydrogen atom, a halogen atom, a cyano group, a hydroxylgroup, a lower alkyl group, a lower alkoxy-lower alkyl group, a loweralkanoyl group, a lower alkoxycarbonyl group or a lower alkylsulfonylgroup, R^(1h) is a hydrogen atom, a halogen atom, a cyano group, ahydroxyl group, a lower alkyl group, a lower alkoxy-lower alkyl group, alower alkanoyl group, a lower alkoxycarbonyl group or a loweralkylsulfonyl group, or R^(1g) and R^(1h) together form a lower alkylenegroup, wherein one or two or more methylene groups constituting thelower alkylene group may be independently replaced by an oxygen atom, asulfur atom, a sulfinyl group, a sulfonyl group, a carbonyl group or agroup of —N(R^(1i))—, or substituted by a halogen atom or a lower alkylgroup; R^(1i) is a hydrogen atom, a lower alkyl group or a halo-loweralkyl group, provided that the compounds wherein R¹⁰ is a methyl groupand R²⁰ is an unsubstituted phenyl group are excluded. 3-8. (canceled)9. The method of claim 2 comprising a compound, or a salt or esterthereof, wherein R¹⁰ is an allyl group, a 2-methyl-2-propenyl group or a3-methyl-2-butenyl group.
 10. The method of claim 2 comprising acompound, or a salt or ester thereof, wherein R²⁰ is a phenyl group, athienyl group, a pyrazolyl group or a pyridyl group, which is optionallysubstituted with a substituent selected from a group consisting of ahalogen atom, a cyano group, a nitro group, a carboxyl group, a group of-Q⁴-A⁴(R^(1g))R^(1h) and a group of -Q⁵-Ar^(a).
 11. The method of claim2 comprising a compound, or a salt or ester thereof, wherein R²⁰ is aphenyl or pyridyl group having a group of -Q⁴-A⁴(R^(1g))R^(1h).
 12. Themethod of claim 2 comprising a compound, or a salt or ester thereof,wherein in the group of the formula -Q¹-A¹-Q²-A²(R^(1a))R^(1b), (i) A¹,Q¹ and Q² are a single bond, A² is a nitrogen atom, and R^(1a) andR^(1b) together form a lower alkylene group wherein one or two methylenegroups constituting the lower alkylene group may be independentlyreplaced by an oxygen atom, a sulfonyl group, a carbonyl group or agroup of —N(R^(1c))—, or substituted by a hydroxyl group; (ii) A¹, Q¹and Q² are a single bond, A² is a methine or 1-vinyl-2-ylidene groupoptionally substituted by a hydroxyl group, and R^(1a) and R^(1b)together form a lower alkylene group wherein one methylene groupconstituting the lower alkylene group is replaced by a group of—N(R^(1c))—; (iii) A¹ is an oxygen atom, A² is a methine group, Q¹ andQ² are a single bond, and R^(1a) and R^(1b) together form a loweralkylene group wherein one methylene group constituting the loweralkylene group is replaced by a group of —N(R^(1c))—; (iv) A¹ is anoxygen atom, A² is a nitrogen atom, Q¹ is a single bond, Q² is anethylene group, R^(1a) is a lower alkyl group, and R^(1b) is a loweralkyl group; or (v) A¹ and Q² are a single bond, A² is a nitrogen atom,Q¹ is a methylene group, R^(1a) is a lower alkyl group, and R^(1b) is alower alkyl group.
 13. The method of claim 1 comprising a compound, or asalt or ester thereof, wherein R²⁰ is a phenyl or pyridyl group having agroup of -Q⁴-A⁴(R^(1g))R^(1h), and the group of-Q¹-A¹-Q²-A²(R^(1a))R^(1b) is selected from the formula (aa1′):


14. The method comprising a compound as claimed in claim 12, or a saltor ester thereof, wherein R^(1c) is a hydrogen atom or a group of-Q³-A³(R^(1d))R^(1e), and in the group of -Q³-A³(R^(1d))R^(1e); (i) A³is a methine group optionally substituted by a hydroxyl group or a loweralkyl group, Q³ is a single bond, R^(1d) is a hydrogen atom or a loweralkyl group, and R^(1e) is a hydrogen atom or a lower alkyl group; (ii)A³ is a methine group, Q³ is a single bond or a lower alkylene group,and R^(1d) and R^(1e) together form a lower alkylene group wherein onemethylene group constituting the lower alkylene group may be replaced bya group of —N(R^(1f))—; (iii) A³ is a methine group optionallysubstituted with a hydroxyl group or a lower alkyl group, Q³ is a loweralkylene group wherein one or two methylene groups constituting thelower alkylene group may be independently replaced by an oxygen atom, acarbonyl group or a sulfonyl group, and/or substituted by a hydroxylgroup, R^(1d) is a hydrogen atom, a halogen atom, a cyano group or alower alkyl group, and R^(1e) is a hydrogen atom, a halogen atom, acyano group or a lower alkyl group; or (iv) A³ is a nitrogen atom, Q³ isa lower alkylene group wherein one methylene group constituting thelower alkylene group is replaced by a carbonyl group, R^(1d) is ahydrogen atom or a lower alkyl group, and R^(1e) is a hydrogen atom or alower alkyl group.
 15. The method of claim 1 comprising a compound, or asalt thereof, which is as follows:3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide,2-allyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,2-allyl-1-[3-(dimethylaminomethyl)phenyl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,2-allyl-6-{[3-hydroxymethyl-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-pyridin-2-yl-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,2-allyl-1-(6-aminopyridin-2-yl)-6-[{4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,2-allyl-6-{[4-(4-ethylpiperazin-1-yl)phenyl]amino}-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,6-{[4-(4-acetylpiperazin-1-yl)phenyl]amino}-2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,2-allyl-6-({4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}amino)-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,2-allyl-1-[6-(2-hydroxy-2-methylpropyl)pyridin-2-yl]-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1-[6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one,N-{[6-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)pyridin-2-yl]methyl}-N-methylmethanesulfonamide.16. The method of claim 1 wherein the compound, or a salt thereof, is3-(2-allyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl)-N,N-dimethylbenzamide.17. The method of claim 1 wherein the compound, or a salt thereof, is2-allyl-6-{[3-(hydroxymethyl)-4-(4-methylpiperazin-1-yl)phenyl]amino}-1-(3-thienyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.18. The method of claim 1 wherein the compound, or a salt thereof, is2-allyl-1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.19. The method of claim 1 wherein the compound, or a salt thereof, is1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-2-(2-propynyl)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.20. The method of claim 1 wherein the compound, or a salt thereof, is1-[6-(1-hydroxy-1-methylethyl)pyridin-2-yl]-2-isopropyl-6-{[4-(1-methylpiperidin-4-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.21. The method of claim 1 wherein the compound, or a salt thereof, is2-allyl-1-[6-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-2-yl]-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one.22-29. (canceled)
 30. The method of claim 1 which further comprisesradiation therapy, and/or an anticancer agent selected from the groupconsisting of anticancer alkylating agents, anticancer antimetabolites,anticancer antibiotics, plant-derived anticancer agents, anticancerplatinum-coordinated complex compounds, anticancer camptothecinderivatives, anticancer tyrosine kinase inhibitors, monoclonalantibodies, biological response modifiers, and other anticancer agents,wherein: the anticancer alkylating agents are selected from the groupconsisting of nitrogen mustard N-oxide, cyclophosphamide, ifosfamide,melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine,nimustine, temozolomide, and carmustine; the anticancer antimetabolitesare selected from the group consisting of methotrexate, 6-mercaptopurineriboside, mercaptopurine, 5-fluorouracil, tegafur, doxifluridine,carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1,gemcitabine, fludarabine, and pemetrexed disodium; the anticancerantibiotics are selected from the group consisting of actinomycin D,doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin,mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatinstimalamer, idarubicin, sirolimus, and valrubicin; the plant-derivedanticancer agents are selected from the group consisting of vincristine,vinblastine, vindeshine, etoposide, sobuzoxane, docetaxel, paclitaxel,and vinorelbine; the anticancer platinum-coordinated complex compoundsare selected from the group consisting of cisplatin, carboplatin,nedaplatin, and oxaliplatin; the anticancer camptothecin derivatives areselected from the group consisting of irinotecan, topotecan, andcamptothecin; the anticancer tyrosine kinase inhibitors are selectedfrom the group consisting of gefitinib, imatinib, and erlotinib; themonoclonal antibodies are selected from the group consisting ofcetuximab, bevacizumab, rituximab, bevacizumab, alemtuzumab, andtrastuzumab; the interferons are selected from the group consisting ofinterferon α, interferon α-2a, interferon α-2b, interferon (3,interferon γ-1a, and interferon γ-n1, the biological response modifiersare selected from the group consisting of krestin, lentinan, sizofuran,picibanil, or ubenimex, and the other anticancer agents are selectedfrom the group consisting of mitoxantrone, L-asparaginase, procarbazine,dacarbazine, hydroxycarbamide, pentostatin, tretinoin, alefacept,darbepoetin alfa, anastrozole, exemestane, bicalutamide, leuprorelin,flutamide, fulvestrant, pegaptanib octasodium, denileukin diftitox,aldesleukin, thyrotropin alfa, arsenic trioxide, bortezomib,capecitabine, and goserelin.
 31. (canceled)
 32. The method of claim 1wherein the cancer is selected from the group consisting of braincancer, cervicocerebral cancer, esophageal cancer, thyroid cancer, smallcell cancer, non-small cell cancer, breast cancer, lung cancer, stomachcancer, gallbladder cancer, bile duct cancer, liver cancer, pancreaticcancer, colon cancer, rectal cancer, ovarian cancer, choriocarcinoma,uterus body cancer, uterocervical cancer, renal cancer, pelvis cancer,ureter cancer, bladder cancer, prostate cancer, penis cancer, testiclescancer, fetal cancer, Wilms' cancer, skin cancer, malignant melanoma,neuroblastoma, osteosarcoma, Ewing's tumor, soft part sarcoma, acuteleukemia, chronic lymphatic leukemia, chronic myelocytic leukemia andHodgkin's lymphoma.
 33. The method of claim 32 wherein the cancer isselected from the group consisting of breast cancer, lung cancer,pancreatic cancer, colon cancer, ovarian cancer, acute leukemia, chroniclymphatic leukemia, chronic myelocytic leukemia and Hodgkin's lymphoma.34. The method of claim 33 wherein the cancer is ovarian cancer.